Substituted benzamide derivatives and their use as anticonvulsants

ABSTRACT

This invention relates to substituted benzamido-heterocyclic compounds of general formula (I) having an alkoxy substituent at the C2 position of the benzamido group and various substituents at positions C4 and C5, being optionally substituted on the N atom of the heterocyclic system, and where the unsaturated ring of the heterocyclic system is a 5,6, 7 or 8-membered ring. Also to the use of these compounds as anticonvulsants in certain medical conditions, and to processes for making them.

This application is a 371 of PCT/EP97/03131, filed Jun. 13, 1997.

This invention relates to novel compounds, to processes for preparingthem, and to their use as therapeutic agents.

U.S. Pat. No. 4,022,900 (Marion), FR-A-2004748 (Marion) and DE-A-2101691(Marion) disclose benzamido-tetrahydroisoquinolines havinganti-hypertensive and vasodilator properties, including the compound5-(2,4,5-trimethoxy-benzamido)-2-methyl-1,2,3,4-tetrahydroisoquinolin,which can also be expressed as2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide.

It as now been surprisingly found that benzamide compounds of formula(I) below possess anti-convulsant activity and are therefore believed tobe useful in the treatment and/or prevention of anxiety, mania,depression, panic disorders and/or aggression, disorders associated witha subarachnoid haemorrhage or neural shock, the effects associated withwithdrawal from substances of abuse such as cocaine, nicotine, alcoholand benzodiazepines, disorders treatable and/or preventable withanti-convulsive agents, such as epilepsy including post-traumaticepilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease and other degenerative diseases such as Huntingdon'schorea, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, sleep disorders (includingcircadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles dela Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia,especially trigeminal neuralgia, neuropathic pain, dental pain, cancerpain, inappropriate neuronal activity resulting in neurodysthesias indiseases such as diabetes, MS and motor neurone disease, ataxias,muscular rigidity (spasticity), temporomandibular joint dysfunction, andamyotrophic lateral sclerosis (ALS).

Accordingly, the present invention provides a compound of formula (I) orpharmaceutically acceptable salt thereof: ##STR1## where n and p areindependently integers from 1 to 4 and (n+p) is from 2 to 5;

R¹ is C₁₋₆ alkylO-;

R² is hydrogen, halogen, CN, N₃, trifluoromethyldiazirinyl, CF₃, CF₃O--, CF₃ S--, CF₃ CO--, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄ alkyl-, C₁₋₆ alkylO-, C₁₋₆ alkylCO-, C₃₋₆ cycloalkylCO-,C₃₋₆ cycloalkyl-C₁₋₄ alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄ alkyl-, C₁₋₆ alkylS-, C₁₋₆ alkylSO₂ --, (C₁₋₄ alkyl)₂ NSO₂-- or (C₁₋₄ alkyl)NHSO₂ --;

R³ is hydrogen, halogen, NO₂, CN, N₃, trifluoromethyldiazirinyl, C₁₋₆alkylO-, C₁₋₆ alkylS-, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄alkyl-, C₁₋₆ alkenyl, C₁₋₆ alkynyl, CF₃ CO--, C₁₋₆ alkylCO-, C₃₋₆cycloalkylCO-, C₃₋₆ cycloalkyl-C₁₋₄ alkylCO-, phenyl, phenoxy,benzyloxy, benzoyl, phenyl-C₁₋₄ alkyl-, or --NR⁵ R⁶ were R⁵ is hydrogenor C₁₋₄ alkyl, and R⁶ is hydrogen, C₁₋₄ alkyl, --CHO, --CO₂ C₁₋₄ alkylor --COC₁₋₄ alkyl;

R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl, or C₁₋₆ alkynyl;

but excluding the compound2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide.

The compounds of this invention are typically(tetrahydroisoquinolin-5-yl)benzamides,(tetrahydroisoquinolin-6-yl)benzamides,(tetrahydroisoquinolin-7-yl)benzamides or(tetrahydroisoquinolin-8-yl)benzamides, especially(tetrahydroisoquinolin-7-yl)benzamides, and most suitably(tetrahydroisoquinolin-5-yl)benzamides; or(dihydroisoindol-4-yl)benzamides; or(tetrahydro-3-benzazepin-6-yl)benzamides.

In the formula (I), R¹ alkoxy groups are typically based on straightchain alkyl groups, but in general alkyl groups may be straight chain orbranched. Aromatic rings, especially the aromatic ring in the bicyclicheterocyclic moiety in formula (I) and phenyl groups, including phenylgroups that are part of other moieties, in R² and R³ may optionally besubstituted with one or more independently selected halogen or C₁₋₆alkyl, C₁₋₆ alkoxy or C₁₋₆ alkylcarbonyl.

Suitable C₃₋₆ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

Suitable halo substituents include fluoro, chloro, iodo and bromo.

A suitable group of compounds of formula (I) have

R¹ as methoxy, ethoxy or n-propoxy

R² as hydrogen, methoxy, bromo, chloro, iodo, acetyl, pivaloyl,iso-butyroyl, benzoyl, trifluoromethyl, trifluoroacetyl,n-propylsulfonyl, isopropylsulfonyl or dimethylsulfamoyl

R³ as hydrogen, methyl, ethyl, n-butyl, iso-propyl, t-butyl, phenyl,methoxy, ethoxy, iso-propoxy, n-butoxy, phenoxy, benzyloxy, amino,acetylamino, nitro, benzoyl, iodobenzoyl, chloro or azido

R⁴ as hydrogen, methyl, ethyl or propyl.

In a special class of compounds of formula (I), suitable for use asmechanistic probes, R² or R³ are photolabile groups, such as N₃, benzoyland trifluoromethyldiazirinyl. Also radiolabels such as ¹²⁵ I can beincorporated at R² or R³, and ³ H and ¹²⁵ I can be located at othersuitable positions.

Examples of compounds of formula (I) are:

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-chloro-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-chloro-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-acetylamino-5-bromo-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-bromo-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-azido-5-iodo-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-acetylamino-5-chloro-2-propoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-chloro-2-propoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-acetylamino-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-nitrobenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-iodo-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-benzyloxy-5-chloro-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4,5-dichloro-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-[3-(trifluoromethyl)-3H-diazirin-3-yl]-2-methoxybenzamide

N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-methylbenzamide

N-(2-n-propyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamide

N-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,5-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2-methoxy-4-methylbenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-dimethylsulfamoyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-benzoyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-4-acetylamino-5-chloro-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-4-amino-5-chloro-2-methoxybenzamide

N-(2,3-dihydro-2-methyl-1H-isoindol-4-yl)-5-chloro-2,4-dimethoxybenzamide.

N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-6-yl)-4-tert-butyl-2-methoxy-benzamide

N-(1,2,3,4-tetrahydroisoquinolin-6-yl)-4-tert-butyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-tert-butyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-n-butyl-2-methoxy-5-chloro-benzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxy-5-chlorobenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxy-5-chloro-benzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-phenylbenzamide

N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-iso-propyl-2-methoxybenzamide

N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-tert-butyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-iso-propoxy-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propyl-5-trifluoromethyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propoxy-2-methoxy-5-trifluoromethyl-benzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-iso-propyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)5-iso-butyroyl-2-methoxy-benzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-pivaloyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chloro-2-methoxy-4-iso-propoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-bromo-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-tert-butyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-methyl-5-trifluoromethylbenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chloro-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propoxy-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-dimethylsulfamoyl-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy--iso-propylsulfonylbenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-phenylbenzamide

N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-n-propylsulfonylbenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,4-dimethoxy-5-trifluoromethylbenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-methyl-5-trifluoromethylbenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-acetyl-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-ethyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxy-5-trifluoromethylbenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-n-butoxy-5-chloro-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-iso-propyloxy-5-acetyl-benzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-iso-propoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-iodo-4-trifluoromethyldiazirinylbenzamide

N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-4-azido-5-iodo-2-methoxybenzamide

N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iodo-2-methoxy-4-trifluoromethyldiazirinylbenzamide

N-(7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide

N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide

N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide

N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-trifluoromethyldiazirinylbenzamide

N-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromethyldiazirinylbenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoroacetylbenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-trifluoromethyldiazirinylbenzamide

N-(1,2,3,4-tetrahydroisoquinolin-7-yl)-5-iodo-2-methoxy-4-trifluoromethyldiazirinylbenzamide

N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(4-iodobenzoyl)-2-methoxybenzamide

N-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoromethyldiazirinylbenzamide,

N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-2-methoxybenzamide

N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-methylthiobenzamide

N-(8-Fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-t-butyl-2-methoxybenzamide

N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iso-butyroyl-4-iso-propoxy-2-methoxybenzamide,and

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-n-butoxy-2-methoxybenzamide.

A preferred group of these compounds is

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-chloro-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-bromo-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-iodo-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-bromo-2,4-dimethoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-iso-propoxy-2-methoxy-benzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propyl-5-trifluoromethyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)5-iso-butyroyl-2-methoxy-benzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-pivaloyl-2-methoxybenzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-iso-propyloxy-5-acetyl-benzamide

N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-iso-propoxybenzamide.

N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxy-5-chlorobenzamide,hydrochloride

N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxy-5-trifluoromethylbenzamide,hydrochloride

When synthesised, these compounds are often in salt form, typically thehydrochloride or trifluoroacethate, and such salts also form part ofthis invention. Such salts may be used in preparing pharmaceuticallyacceptable salts. The compounds and their salts may be obtained assolvates, such as hydrates, and these also form part of this invention.

The above-listed compounds and pharmaceutically acceptable saltsthereof, especially the hydrochloride, and pharmaceutically acceptablesolvates, especially hydrates, form a preferred aspect of the presentinvention.

The administration of such compounds to a mammal may be by way of oral,parenteral, sub-lingual, nasal, rectal, topical or transdermaladministration.

An amount effective to treat the disorders hereinbefore describeddepends on the usual factors such as the nature and severity of thedisorders being treated and the weight of the mammal. However, a unitdose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, forexample an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20,30, 40, 50, 60, 80, 100, 200, 300 and 400 mg of the active compound.Unit doses will normally be administered once or more than once per day,for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times aday, such that the total daily dose is normally in the range, for a 70kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the rangeof approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day,for example 1 to 6 mg/kg/day.

It is greatly preferred that the compound of formula (I) is administeredin the form of a unit-dose composition, such as a unit dose oral,including sub-lingual, rectal, topical, nasal, or parenteral (especiallyintravenous) composition.

Such compositions are prepared by admixture and are suitably adapted fororal or parenteral administration, and as such may be in the form oftablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions ornasal sprays or suspensions or suppositories. Orally administrablecompositions are preferred, in particular shaped oral compositions,since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colourants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and othersimilar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbithan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

Oral formulations also include conventional sustained releaseformulations, such as tablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are preparedcontaining the compound and a sterile vehicle. The compound, dependingon the vehicle and the concentration, can be either suspended ordissolved. Parenteral solutions are normally prepared by dissolving thecompound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are alsodissolved in the vehicle. To enhance the stability, the composition canbe frozen after filling into the vial and the water removed undervacuum.

Parenteral suspensions are prepared in substhantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure to ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfacthant or wetting agentis included in the composition to facilithate uniform distribution ofthe compound of the invention.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

Accordingly, in a further aspect, the present invention provides apharmaceutical composition for use in the treatment and/or propylaxis ofanxiety, mania, depression, panic disorders and/or aggression, disordersassociated with a subarachnoid haemorrhage or neural shock, the effectsassociated with withdrawal from substhances of abuse such as cocaine,nicotine, alcohol and benzodiazepines, disorders treatable and/orpreventable with anti-convulsive agents, such as epilepsy includingpost-traumatic epilepsy, Parkinson's disease, psychosis, migraine,cerebral ischaemia, Alzheimer's disease and other degenerative diseasessuch as Huntingdon's chorea, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits associated withh AIDS, sleepdisorders (including circadian rhythm disorders, insomnia & narcolepsy),tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury,tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain,dental pain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias in diseases such as diabetes, MS and motor neuronedisease, ataxias, muscular rigidity (spasticity), temporomandibularjoint dysfunction, and amyotrophic lateral sclerosis (ALS) whichcomprises a compound of formula (I), withhout excluding2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide,or a pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.

The present invention also provides a method of treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substhances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,phychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, MS and motor neurone disease, ataxias, muscular rigidity(spasticity), temporomandibular joint dysfunction, and amyotrophiclateral sclerosis (ALS) comprising administering to the sufferer in needthereof an effective or prophylactic amount of a compound of formula(I), without excluding2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide,or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect the invention provides the use of a compound offormula (I), without excluding2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide,or a pharmaceutically acceptable salt or solvate thereof, for themanufacture of a medicament for the treatment and/or prophylaxis ofanxiety, mania, depression, panic disorders and/or aggression, disordersassociated with a subarachnoid haemorrhage or neural shock, the effectsassociated with withdrawal from substhances of abuse such as cocaine,nicotine, alcohol and benzodiazepines, disorders treatable and/orpreventable with anti-convulsive agents, such as epilepsy includingpost-traumatic epilepsy, Parkinson's disease, psychosis, migraine,cerebral ischaemia, Alzheimer's disease and other degenerative diseasessuch as Huntingdon's chorea, schizophrenia, obsessive compulsivedisorders (OCD), neurological deficits associated with AIDS, sleepdisorders (including circadian rhythm disorders, insomnia & narcolepsy),tics (e.g. Giles de la Tourette's syndrome), traumatic brain injury,tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain,dental pain, cancer pain, inappropriate neuronal activity resulting inneurodysthesias in diseases such as diabetes, MS and motor neuronedisease, ataxias, muscular rigidity (spasticity), temporomandibularjoint dysfunction, and amyotrophic lateral sclerosis (ALS).

In a further aspect the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate, thereofas a therapeutic agent, in particular for the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substhances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,phychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, MS and motor neurone disease, ataxias, muscular rigidity(spasticity), temporomandibular joint dysfunction, and amyotrophiclateral sclerosis (ALS).

Another aspect of the invention provides a process for the preparationof compounds of formula (I), which comprises reacting a compound offormula (II) ##STR2## where n and p are as defined for formula (I) andR^(4A) is R⁴ as defined for formula (I) or a group convertible to R⁴with a compound of formula (III) ##STR3## where Y is Cl or OH, andR^(1A), R^(2A), and R^(3A) are respectively R¹, R², and R³ as definedfor formula (I) or groups convertible to R¹, R², and R³, and wererequired converting a R^(1A), R^(2A), R^(3A) or R^(4A) group to a R¹,R², R³ or R⁴ group, converting one R¹, R², R³ or R⁴ group to another R¹,R², R³ or R⁴ group, converting a hydrochloride salt product to the freebase or another pharmaceutically acceptable salt or converting a freebase product to a pharmaceutically acceptable salt.

Reaction of a compound of formula (III) which is a benzoyl chloridederivative (Y═Cl) will lead directly to the hydrochloride salt. Suitablesolvents include ethyl acethate and tetrahydrofuran. When the compoundof formula (III) is a benzoic acid derivative (Y═OH), conventionalconditions for condensation of aromatic acids with amines may be used,for example reacting the components in a mixture of(dimethylaminopropyl)-ethyl-carbodiimide and hydroxybenzotriazole in asuitable solvent such as dimethyl formamide.

Conversions of an R^(1A), R^(2A), R^(3A) or R^(4A) group to a R¹, R² ;R³ or R⁴ group typically arise when a protecting group is needed duringthe above coupling reaction or during the preparation of the reacthantsby the procedures described below. Interconversion of one R¹, R², R³ orR⁴ group to another typically arises when one compound of formula (I) isused as the immediate precursor of another compound of formula (I) orwhen it is easier to introduce a more complex or reactive substituent atthe end of a synthetic sequence.

Compounds of formula (II) may be prepared from a compound of formula(IV) ##STR4## where X is a leaving group, such as halogen, especiallyBr, or methanesulfonyl, which is reacted with R^(4A) NH₂, were R^(4A) isR⁴ as defined above or an N-protecting group, to obtain compounds offormula (V) ##STR5## and then reduced, for example usinghydrogen/palladium, to obtain compounds of formula (II).

Alternatively, a compound of formula (VI) ##STR6## may be reduceddirectly, for example with lithium aluminium hydride, typically intetrahydrofuran, to obtain a compound of formula (II) or a compound offormula (II) may obtained in a two step procedure were a hydrogenation,typically with hydrogen/palladium, is followed by reduction, againsuitably with lithium aluminium hydride.

When R^(4A) in formula (V) or (VI) is alkenyl or alkynyl, reagents forreduction of NO₂ must be selected so as to selectively reduce NO₂without affecting the R^(4A) group. It may be more suitable that R^(4A)in formula (V) or (VI) is an N-protecting group, that may be removed atan appropriate point in the reaction and replaced by a desired R⁴ groupby conventional methods.

Compounds of formulae (UV) and (VI) and the reagents used arecommercially available, or can be prepared from commercially availablematerials using conventional procedures described in the literature, andas illustrated below.

More specifically, compounds of formula (II) in which n=1 and p=2 or n=2and p=1 are tetrahydroisoquinolines and may be prepared from thecorresponding unsaturated compound of formula (VII) ##STR7## by reactionwith a compound R^(4A) Z were Z is a leaving group such as halogen,especially iodo, or tosylate to obtain an intermediate of formula (VIII)##STR8## which can be reduced, for example using sodium borohydride, tothe compound of formula (II). Alternatively the compound of formula(VIII) can be hydrogenated, for example using hydrogen at 50 psi in asolution of acetic/sulphuric acid with a platinum oxide catalyst.

Another route is from a precursor of formula (IX) ##STR9## which can bereacted with R^(4A) Z, preferably as a tosylate, to obtain theintermediate of formula (X) ##STR10## which can then be hydrogenatedunder the conditions previously described to prepare the compound offormula (II).

When R^(4A) is hydrogen, the compound of formula (II) can be obtained bydirect hydrogenation of the compounds of formula (VII) or (IX), usingthe reagents already described. The NH may be protected conventionally,for example by making R^(4A) t-butoxycarbonyl, prior to formation of thebenzamide, and then deprotected under sthandard conditions, for exampleusing trifluoroacetic acid/methylene chloride.

Compounds of formulae (VII) and (IX) and the reagents used arecommercially available, or can be prepared from commercially availablematerials using conventional procedures described in the literature.

Compounds of formula (II) in which n=1 and p=1 areamino-dihydroisoindolines. Such compounds may be prepared from compoundsof formula (XI) ##STR11## by forming a leaving group, such as bromo, onthe methyl groups, and reacting with an amine R^(4A) NH₂ to form thesaturated heterocyclic ring, followed by reduction of the nitro group.For example, the compound of formula (XII) ##STR12## may be formed byrefluxing the compound of formula (XI) with N-bromosuccinimide/carbontetrachloride in the presence of a light source and/or a radicalinitiator such as t-butyl perbenzoate. The product (XII) can be reactedwith R^(4A) NH₂ in methylene dichloride to obtain the compound offormula (XIII) ##STR13## This can be converted to an aminoisoindoline offormula (II) by reduction with hydrogen and a palladium catalyst inethanol. This route is based on the procedure disclosed in U.S. Pat. No.5,436,250.

Alternative routes to dihydroisoindolines of formula (II) via a compoundof formula (VI) were n=1 and p=1 can be found in Watjen et al, Biomed.Lett. 1994, 4(2), 371 and Knefeli et al, Arch. Pharm. 1989, 322, 419.

Compounds of formula (II) in which (n+p)=4 areamino-tetrahydrobenzazepines. Such compounds may be prepared from acompound of formula (XIV) ##STR14## where R⁷ is C₁₋₄ alkyl, typicallymethyl or ethyl, which is reacted with diborane in a suitable solventsuch as tetrahydrofuran to give a compound of formula (XV) ##STR15##Further reaction with methanesulfonyl chloride in pyridine gives acompound of formula (XVI) ##STR16## which is a compound of formula (IV)in which X is methanesulfonyl (OMs). This can be reacted with R^(4A) NH₂in a solvent such as dimethylformamide to obtain a compound of formula(V) with the appropriate n/p values for an amino-tetrahydrobenzazepine.

In this reaction R^(4A) is suitably a protecting group such as benzylwhich is easily replaceable by desired R⁴ groups. Further reaction withhydrogen and a palladium catalyst in acetic acid converts the NO₂ groupto NH₂ and results in a compound of formula (II). If the R^(4A) group informula (XVII) is benzyl then the corresponding formula (II) compoundwill contain a R⁴ hydrogen group, which can be used as a starting pointfor additional R⁴ groups by conventional interconversions. This reactionscheme is based on the disclosure of EP-A-0002624 to which reference isdirected, and which specifically discloses preparation ofaminotetrahydrobenzazepines of formula (II) in which n=1 and p=3 (orvice versa), or as described by R. M. DeMarinis et al, J. Med. Chem.,1984, 27, 918 for n=p=2.

Compounds of formula (III) can be prepared by further substitution ofcommercially available benzoic acid derivatives using conventionalprocedures, by analogy with the procedures set out in the Preparationsbelow. Suitable starting materials are 2,4-dimethoxy benzoic acid,2-methoxy 4-amino benzoic acid and 2-methoxy 4-chloro benzoic acid.

The preparation of compounds of this invention is further illustrated bythe following Preparations and Examples. The utility of compounds ofthis invention is shown by the Pharmacological Data that follow theExamples.

PREPARATION 1 5-Amino-2-methylisoquinolinium Iodide

To a solution of 5-aminoisoquinoline (14.4 g, 100 mmol) in acetone (300ml) was added iodomethane (14.4 ml). The solution was briefly stirredand then allowed to sthand for 2h. The yellow precipithate was thenfiltered, washed with acetone and dried to afford the title compound asa yellow solid (18.8 g).

PREPARATION 2 5-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline

To an ice cold solution of 5-amino-2-methylisoquinolinium iodide (18.8g, 65 mmol) in methanol (1.5L) and water (60 ml) was added sodiumborohydride (17.8 g, 0.47 mol) portionwise over 2h. The mixture was thenallowed to stir at room temperature for 18h before concentration invacuo and partitioning of the residue between water and dichloromethane.The organic layer was dried over sodium sulfate and concentrated invacuo to afford the title compound (8.87 g).

PREPARATION 3 4-Azido-5-iodo-2-methoxybenzoic Acid

To a solution of 4-amino-5-iodo-2-methoxybenzoic acid (300 mg, 1.02mmol) in trifluoroacetic acid (4 ml) at 5° C., was added sodium nitrite(283 mg, 4.1 mmol) portionwise, and the mixture allowed to stir for 30min. Sodium azide (200 mg, 3.07 mmol) was then added portionwise and themixture stirred for a further 30 min at 0° C. The mixture was dilutedwith water, and a yellow solid precipithated. The solid was filtered,washed with cold water and dried, to afford the title compound (274 mg,84%).

PREPARATION 4 4,5-Dichloro-2-methoxybenzoic Acid

To an ice cold solution of 4-chloro-2-methoxybenzoic acid (1.0 g, 5.36mmol) in trifluoroacetic acid (7 ml) was added N-chloromorpholine (0.67g, 5.5 mmol) dropwise, maintaining the internal temperature below 10° C.After stirring overnight at room temperature the trifluoroacetic acidwas removed in vacuo and the residue partitioned between ethyl acethateand water. The organic layer was dried over magnesium sulfate,concentrated in vacuo and the residue recrystallised from methanol toafford the title compound as a white solid (200 mg).

PREPARATION 5 5-Chloro-2,4-dimethoxybenzoic Acid

The title compound was prepared in an analogous fashion to Preparation 4from 2,4-dimethoxybenzoic acid (1.3 g). Recrystallisation of the crudeproduct from methanol afforded the title compound as a white solid (1.3g).

PREPARATION 6 5-Bromo-2,4-dimethoxybenzoic Acid

To a solution of 2,4-dimethoxybenzoic acid (4.0 g, 0.022 mol) inchloroform (60 ml) was added bromine (1.13 ml, 0.022 mol) in chloroform(20 ml) dropwise. After stirring overnight at room temperature theprecipithate was filtered off and dried to afford the title compound asa white solid (2.87 g).

PREPARATION 7 (5-Bromo-2-methoxybenzyloxy)-tert-butyldimethylsilane

To a solution of 5-bromo-2-methoxybenzyl alcohol (1.0 g, 4.6 mmol) andimidazole (470 mg, 7.01 mmol) in DMF (15 ml) was addedtert-butyldimethylsilyl chloride (1.04 g, 6.91 mmol). The mixture wasallowed to stir for 4 h, poured onto water (100 ml) and extracted withether (3×30 ml). The combined organic phases were washed with water (50ml), brine (50 ml), dried over sodium sulfate and evaporated underreduced pressure to leave a pale yellow oil. This was purified bychromatography (SiO₂, 5% ether/petrol), to give the title compound (1.46g, 96%) as a colourless oil.

PREPARATION 8(5-Trifluoroacetyl-2-methoxybenzyloxy)-tert-butyldimethylsilane

To a solution of 5-bromo-2-methoxybenzyloxy)-tert-butyldimethylsilane(1.0 g, 3.02 mmol) in THF (5 ml) at -78° C., was added n-BuLi (2.26 mlof a 1.6 M solution in penthane, 3.62 mmol) dropwise over 10 min. Thesolution was allowed to stir for a further 1 h at -78° C., to give abright yellow solution. N,N-diethyltrifluoroacetamide (561 mg, 3.32mmol) in THF (2 ml) was added dropwise over 30 min, and the solution wasstirred for a further 1 h at -78° C. Saturated aqueous ammonium chloride(5 ml) was added and the mixture allowed to warm to room temperature,and extracted with ether (3×10 ml). The combined organic phases werewashed with water (10 ml), brine (10 ml), dried over sodium sulfate andevaporated in vacuo. The resulting residue was purified bychromatography (SiO₂, 5% ether/petrol) to give the title compound (0.99g, 94%) as a white solid.

PREPARATION 9 (E,Z)-1-[3-(tert-Butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-2,2,2-trifluoroethanoneOxime

A mixture of(5-trifluoroacetyl-2-methoxybenzyloxy)-tert-butyldimethylsilane (1.0 g,2.87 mmol), hydroxylamine hydrochloride (240 mg, 3.44 mmol), pyridine(18 ml) and ethanol (9 ml) were heated at reflux for 4 h. The resultingmixture was evaporated in vacuo and the residue purified bychromatography (SiO₂, 20% ether/petrol), to give an approximately 3:2inseparable isomeric mixture of (E, Z)-1-[3-(tert-butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-2,2,2-trifluoroethanone oximes (1.02 g, 98%)as a colourless oil.

PREPARATION 10 (E,Z)-(4-Toluensulfonyl)-1-[3-(tert-butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-2,2,2-trifluoroethanone Oxime

To a solution of (E,Z)-1-[3-(tert-butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-2,2,2-trifluoroethanoneoximes (1.0 g, 2.75 mmol), triethylamine (340 mg, 3.36 mmol), DMAP (31mg, 0.25 mmol) in dichloromethane (5 ml) at 0° C., was added tosylchloride (627 mg, 3.29 mmol) portionwise. The mixture was stirred for 1h at room temperature and then poured onto water (10 ml). The layerswere separated, and the aqueous phase extracted with dichloromethane(3×10 ml). The combined organic phases were washed with water (10 ml),dried (Na₂ SO₄) and evaporated in vacuo. The residue was purified bychromatography (SiO₂, 20% ether/petrol) to give an inseparable mixtureof (E,Z)-(4-toluensulfonyl)-1-[3-(tert-butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-2,2,2-trifluoroethanoneoximes (1.39 g, 98%) as a colourless oil.

PREPARATION 113-[3-(tert-Butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-3-trifluoromethyldiaziridine

A solution of (E,Z)(4-toluensulfonyl)-1-[3-(tert-butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-2,2,2-trifluoroethanoneoximes (517 mg, 1 mmol) in ether (5 ml) was stirred with liquid NH₃ (15ml) in a bomb for 4 h at room temperature. The mixture was then filteredand the solid washed with ether. The filtrate was evaporated in vacuoand the residue purified by chromatography (SiO₂, 20% ether/petrol) togive the title compound (350 mg, 97%) as a pale yellow oil.

PREPARATION 123-[3-(tert-Butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-3-trifluoromethyl-3H-diazirine

A mixture of3-[3-(tert-butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-3-trifluoromethyldiaziridine(200 mg, 0.55 mmol) and freshly prepared Ag₂ O(255 mg, 1.1 mmol) inether (3 ml) was stirred for 24 h. The solid was filtered, washed withether, and the filtrate evaporated in vacuo. The resulting residue waspurified by chromatography (SiO₂, 10% ether/petrol) to give the titlecompound (187 mg, 94%) as a colourless oil.

PREPARATION 13 2-Methoxy-5-(3-trifluoromethyl-3H-diazirin-3-yl)benzoicAcid

A solution of 3-[3-(tert-butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-3-trifluoromethyl-3H-diazirine(150 mg, 0.41 mmol) in methanol (5 ml) was stirred for 20 min with conc.HCl (2 drops). The solution was poured onto saturated aqueous sodiumbicarbonate (10 ml) and extracted with dichloromethane (3×5 ml). Thecombined organic extracts were dried over sodium sulfate and evaporatedunder reduced pressure. The residue was taken up in dioxane (3 ml) andaqueous potassium hydroxide (2.5 ml of a 0.2M solution), potassiumpermanganate (98 mg, 0.62 mmol) was added and the mixture stirred for 4h. The mixture was filtered through a pad of Celite and washed withwater. The filtrate was extracted with ether (2×10 ml). The aqueousphase was brought to pH 1, extracted with ether (2×10 ml) and theseextracts were dried over sodium sulfate and evaporated in vacuo to givethe title compound (77 mg, 72%) as an off white solid.

PREPARATION 14 5-Amino-1,2,3,4-tetrahydroisoquinoline

A solution of 5-aminoisoquinoline (10 g, 69 mmol) in glacial acetic acid(150 ml) and concentrated sulfuric acid (1 ml) was hydrogenated overplatinum oxide (1 g) at 55 psi for 20h. The acetic acid was then removedin vacuo and the residue treated with saturated aqueous potassiumcarbonate (100 ml) and extracted with dichloromethane. The organic layerwas dried over sodium sulfate and concentrated in vacuo to afford thetitle compound (6.45 g).

PREPARATION 155-Amino-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline

An ice cold solution of 5-amino-1,2,3,4-tetrahydroisoquinoline (6.45 g,44 mmol) in 1,4-dioxane (250 ml) was treated with 3M sodium hydroxide(14.7 ml, 44 mmol), and di-tert-butyl-dicarbonate (9.57 ml, 44 mmol) andthe solution was stirred at room temperature overnight. The reactionmixture was then poured into water (400 ml) and extracted with ether.The organic phases were dried over sodium sulfate and concentrated invacuo to afford a brown oil which solidified on sthanding and wasrecrystallised from ethanol/petrol to afford the title compound as anoff white crystalline solid (5.1 g).

PREPARATION 16 5-Chloro-2,4-dimethoxybenzoyl Chloride

A solution of 5-chloro-2,4-dimethoxybenzoic acid (6.4 g) indichloromethane (250 ml) was treated with thionyl chloride (30 ml) andthe mixture heated at reflux for 18h. Removal of volatile material invacuo afforded the title compound as a white solid (6.6 g).

PREPARATION 175-Chloro-2,4-dimethoxy-N-[2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide

To a solution of5-amino-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline (1 g, 4mmol) in dichloromethane (30 ml) and triethylamine (3 ml) was added5-chloro-2,4-dimethoxybenzoyl chloride (1.03 g, 4.4 mmol). Afterstirring at room temperature for 2h the reaction mixture was dilutedwith dichloromethane (75 ml) and washed with saturated aqueous sodiumbicarbonate. The organic layer was dried over magnesium sulfate,concentrated in vacuo and the residue recrystallised from ethylacethate/petrol to afford the title compound as a colourless crystallinesolid (1.3 g).

PREPARATION 18 5-Chloro-2-methoxy-4-methylbenzoic Acid

The title compound was prepared in an analogous manner to Preparation 4from 2-methoxy-4-methylbenzoic acid (3.0 g, 0.018 mol). Purification ofthe crude product using a chromatotron (SiO₂, 10% ethyl acethate inhexane) afforded the title compound as a white solid (0.40 g)

PREPARATION 19 5-Amino-2-ethyl-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared by treatment of 5-aminoisoquinoline withiodoethane followed by reduction with sodium borohydride usingprocedures analogous to those described in Preparation 1 and Preparation2.

PREPARATION 20 5-Amino-2-propyl-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared by treatment of 5-aminoisoquinoline withiodopropane followed by reduction with sodium borohydride usingprocedures analogous to those described in Preparation 1 and Preparation2.

PREPARATION 21 4-Benzyloxy-5-chloro-2-methoxybenzoic Acid

A solution of chlorine (5.1 g) in acetic acid (100 ml) was addeddropwise to a solution of methyl 4-benzyloxy-2-methoxybenzoate (10 g) inacetic acid (40 ml) whilst maintaining the temperature at 20-25° C. Themixture was poured into ice-water and extracted with dichloromethane.The organic extract was dried over sodium sulfate and concentrated invacuo. The resulting crude material was suspended in ethanol (500 ml)and treated with 10% aqueous sodium hydroxide (16 ml). The mixture washeated at reflux overnight and then concentrated in vacuo. The residuewas treated with excess 5M HCl and extracted into dichloromethane. Theextract was dried (sodium sulfate) and concentrated in vacuo to afford awhite solid which was crystallised from ethanol to give the titlecompound (6.3 g).

PREPARATION 22 4-Hydroxy-2-methoxybenzoic Acid Methyl Ester

4-Amino-2-methoxy benzoic acid methyl ester (15 g, 82.7 mmol) wasdissolved in sulfuric acid (80 ml of a 25% solution). The solution wascooled in an ice bath and diazotized with saturated sodium nitritesolution (8.57 g, 124 mmol) maintaining the temperature below 5° C. Thediazonium solution was poured slowly into boiling sulphuric acid (1L ofa 3% solution) and the mixture was heated for an additional 5 mins. Themixture was then allowed to cool before being extracted withdichloromethane. The organic extracts were combined, dried over sodiumsulfate and concentrated in vacuo to afford a brown solid (9.7 g).

PREPARATION 23 4-Ethoxy-2-methoxy-benzoic Acid Methyl Ester

To a solution of 4-hydroxy-2-methoxybenzoic acid methyl ester (4.17 g,22 mmol) in DMF (50 ml) under argon was added potassium carbonate (6.33g, 4.6 mmol) followed by iodoethane (7.15 g, 4.6 mmol). The mixture wasthen heated to 50° C. under argon for 12h. On cooling the mixture waspoured into a large excess of water and extracted with ether. Thecombined organic extracts were dried over sodium sulfate andconcentrated in vacuo to afford the title compound as a brown oil (4.8g).

PREPARATION 24 5-Chloro-4-ethoxy-2-methoxybenzoic Acid

Trifluoroacetic acid (35 ml) was cooled in an ice bath.4-ethoxy-2-methoxy-benzoic acid methyl ester (4.85 g, 23 mmol) was thenadded slowly. N-chloromorpholine (3.64 g, 29.9 mmol) was then addeddropwise maintaining the reaction mixture temperature below 10° C. Theice bath was removed and the mixture stirred under argon for 12h at roomtemperature. The solvent was then removed in vacuo and the residue takenup in ethyl acethate and washed with water. The organic layer was driedover sodium sulfate and concentrated in vacuo to afford a brown oilwhich was triturated with ether and 60/80 petrol. The resulting brownsolid was then recrystallised from 60/80 petrol, taken up into ether andwashed with sodium hydroxide solution (2M). The organic layer was driedover sodium sulfate and concentrated in vacuo to afford the methyl esteras a pale yellow solid (0.9 g). A mixture of this ester (0.9 g, 3.6mmol), methanol (22 ml) and sodium hydroxide solution (20 ml, 2M) washeated to 70° C. overnight. On cooling the mixture was acidified to pH6-7 and the solvent was removed in vacuo. The residue was taken up inethanol and the inorganic solid filtered off. The filtrate wasconcentrated in vacuo to afford the title compound as a pale brown solid(0.44 g).

PREPARATION 25 5-Bromo-2-methoxy-4-methylbenzoic Acid

The title compound was prepared in an analogous manner to Preparation 6from 2-methoxy-4-methylbenzoic acid (3.0 g, 0.018 mol).Recrystallisation of the crude product from dichloromethane afforded thetitle compound as a white solid (0.99 g).

PREPARATION 26[4-(tert-Butyldimethylsilanyloxymethyl)-3-methoxyphenyl]-phenylmethanol

To 2-(tert-Butyldimethylsilanyloxymethyl)-5-bromoanisole (500 mg, 1.51mmol) in THF (10 ml) at -78° C. was added n-BuLi (1.13 ml of a 1.6Msolution in penthane, 1.81 mmol) and the mixture allowed to stir for 1 hat -78° C. Benzaldehyde (176 mg, 1.66 mmol) was added and the mixtureallowed to warm to room temperature and stirred for 1 h. Water (20 ml)was added and the mixture extracted with ether (3×10 ml). The combinedextracts were washed with water (10 ml), brine (10 ml), dried (Na₂ SO₄)and evaporated under reduced pressure. The resulting residue waspurified by chromatography (SiO₂, 50% ether/petrol) to give the titlecompound as a colourless oil (303 mg, 56%).

PREPARATION 27[5-(tert-Butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-phenylmethanol

The title compound was prepared in an analogous manner to Preparation 26from 2-(tert-Butyldimethylsilanyloxymethyl)-4-bromoanisole (500 mg, 1.51mmol). The crude product was purified by chromatography (SiO₂, 50%ether/petrol) to give the title compound as a colourless oil (63%).

PREPARATION 28 4-Benzoyl-2-methoxybenzoic Acid

A solution of4-(tert-butyldimethylsilanyloxymethyl)-3-methoxyphenyl]-phenylmethanol(200 mg, 0.56 mmol) in THF (5 ml) was stirred with 5N HCl (5 ml) for 1h. The mixture was poured onto saturated aqueous sodium bicarbonate (10ml) and extracted with ether (3×10 ml). The combined organic extractswere dried (Na₂ SO₄), and evaporated under reduced pressure. The residuewas taken up in dioxane (4 ml) and aqueous KOH (5.6 ml of a 0.2Msolution), potassium permanganate (266 mg, 1.68 mmol) was added and themixture stirred for 4 h. The mixture was filtered through a pad ofCelite and washed with water. The filtrate was extracted with ether(2×10 ml) and the aqueous phase was brought to pH 1 and extracted withether (2×10 ml). These extracts were dried over sodium sulfate andevaporated in vacuo to afford the title compound as a white foam (102mg, 71%).

PREPARATION 29 5-Benzoyl-2-methoxybenzoic Acid

The title compound was prepared in an analogous manner to Preparation 28from[5-(tert-butyldimethylsilanyloxymethyl)-4-methoxyphenyl]-phenylmethanol(200 mg, 0.56 mmol).

The title compound was obtained as a white foam (74%).

PREPARATION 30 3-Nitro-N-methylphthalimide

A solution of 3-nitrophthalimide (Aldrich)(1.78 g, 0.01 mol) in dryN,N-dimethylformamide (20 ml) was added dropwise to a stirred suspensionof sodium hydride (0.36 g of an 80% dispersion in oil; 0.012 mol) in dryN,N-dimethylformamide (10 ml) under argon. The mixture was stirred atroom temperature for 30 min and then treated with iodomethane (0.75 ml,0.012 mol). After stirring overnight the reaction was poured intoice-water and extracted with dichloromethane (4×50 ml). The combinedextracts were washed with water followed by brine, then dried oversodium sulfate and concentrated in vacuo. The residue was treated withwater, and the resulting precipithate was removed by filtration andwashed with water. After drying in a vacuum dessicator over silica gelthe title compound was obtained as a yellow solid (1.64 g).

PREPARATION 31 4-Amino-2,3-dihydro-2-methyl-1H-isoindole

A solution of 3-nitro-N-methylphthalimide (0.58 g, 2.8 mmol) in drytetrahydrofuran (10 ml) was added dropwise to a stirred suspension oflithium aluminium hydride (0.64 g, 16.8 mmol) under argon. The mixturewas stirred at room temperature for 2h and then heated under gentlereflux for 2.5h. The reaction was quenched by addition of wet diethylether followed by a minimum amount of water. The precipithated aluminiumsalts were removed by filtration. The filtrate was concentrated in vacuoto give the title compound as a brown oil (400 mg) which was useddirectly in the next stage (Example 31).

PREPARATION 32 6-Amino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine

9-Amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, preparedaccording to R. M. DeMarinis et al, J. Med. Chem., 1984, 27, 918, (0.190g, 0.90 mmol) was dissolved in 10% acetic acid in methanol (50 ml) and10% Pd/C (150 mg) added. The mixture was stirred at room temperature,under hydrogen/atmos pressure for 4h, then filtered through Kieselguhrand evaporated in vacuo. Residual material was taken up intodichloromethane and 5% NaHCO₃ solution; the organic layer was washedwith brine, dried (Na₂ SO₄) and evaporated in vacuo to afford the titlecompound as a colourless oil (133 mg).

PREPARATION 336-Amino-2-(t-butyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline

A solution of 6-amino-1,2,3,4-tetrahydroisoquinoline (0.74 g, 5 mmol) in1,4-dioxan (50 ml) containing 5M-NaOH (1 ml) was stirred at 5° C. andtreated with di-t-butyl dicarbonate (1.09 g, 5 mmol). After 20 min atroom temperature the product was extracted with ethyl acethate and thematerial in the organic layer gave a brown gum which was chromatographedon Kieselgel 60 in 5% methanol:dichloromethane. The title compound wasobtained as a pale gum (0.55 g).

¹ H NMR (CDCl₃) δ: 1.49 (9H, s), 2.74 (2H, t), 3.60(4H, br), 4.46 (2H,s), 6.47 (1H, d), 6.55(1H, dd), 6.90 (1H, d).

PREPARATION 34 4-tert-Butyl-phenoxyacethate

A mixture of 3-tert-butylphenol (25.25 g, 0.1680 mole), acetic anhydride(34.31 g, 0.336 mole) and sodium acethate (13.78 g, 0.1680 mole) washeated at 100° C. for 2h. On cooling the mixture was poured into water(200 ml) and extracted with ethyl acethate (200 ml). The combinedorganic extracts were dried over sodium sulfate and concentrated invacuo to afford the acethate compound as an oil (33.33 g).

PREPARATION 35 4-tert-Butyl-2-hydroxy Acetophenone

A mixture of the acethate of Preparation 34 (33.23 g, 0.173 mole) andAlCl₃ (25.61 g, 0.192 mole) was placed in an oil bath preheated to 120°C. and stirred mechanically. Then the oil bath temperature was raised to165° C. and maintained for 45 min before being allowed to cool to 120°C. Then water was added dropwise into the reaction mixture (4×250 ml) tosteam distil the product (bath temp 190-200° C.). The distillate wasextracted with ether and the combined organic extracts were dried oversodium sulfate and concentrated in vacuo to afford4-tert-butyl-2-hydroxy acetophenone as an oil (18.05 g).

PREPARATION 36 4-tert-Butyl-2-methoxy Acetophenone

A suspension of 4-tert-butyl-2-hydroxy acetophenone (12.65 g), potassiumcarbonate (13.14 g) and dimethyl sulphate (8.99 ml) in acetone (200 ml)was refluxed for 48h. After cooling, the mixture was filtered. Thesolvent was then removed in vacuo and the residue taken up indichloromethane and washed with brine. The organic layer was dried oversodium sulphate and concentrated in vacuo to afford a yellow oil (12.05g).

PREPARATION 37 4-tert-Butyl-2-methoxybenzoic Acid

The acetophenone of Preparation 36 (11.0 g, 53 mmol) was added to asolution of sodium hydroxide (28.68 g), sodium hypochlorite (182 ml, 12%w/w) and water (70 ml) at 80° C. with stirring. After heating for 1.25h,the mixture was cooled to 0° C. and a solution of sodium metabisulphite(41.1 g) in water (170 ml) was added. The mixture was stirred for 15 minand then acidified (pH1) with conc. HCl (45 ml). Work-up with ethylacethate gave the title compound as a white solid (8.9 g).

¹ H NMR (DMSO-d⁶) δ: 1.30 (9H, s), 3.85(3H, s), 6.96-7.12 (2H, m), 7.60(1H, d), 12.30-12.60 (1H, br).

PREPARATION 38 4-n-Butyl-2-methoxybenzoic Acid

A mixture of 4-bromo-2-methoxybenzoic acid methyl ester (3.0 g, 0.0122mole), lithium chloride (1.56 g), tetra butyl tin (4.51 g) and bis(triphenyl phosphine palladium (II) chloride (214 mg, 0.3 mmol) wereheated at 100° C. for 24h. The solvent was then removed in vacuo and theresidue taken up in dichloromethane. The black solid was removed byfiltration and the filtrate concentrated in vacuo to give a yellow oil.The oil was purified by column chromatography (Biotage) on silica gelusing 10% ether in hexane to afford a colourless oil (1.63 g). A portionof the foregoing 4-n-butyl-2-methoxybenzoic acid methyl ester (1.50 g)was dissolved in methanol (35 ml) with sodium hydroxide solution (2N, 30ml). The mixture was allowed to stir at room temperature overnight. Thenadded dil. HCl until pH-5. The solvent was then removed in vacuo and theresidue taken up in ethyl acethate and washed with brine. The organiclayer was dried over sodium sulfate and concentrated in vacuo to affordan oil (1.02 g).

PREPARATION 39 4-n-Butyl-2-methoxy-5-chlorobenzoic Acid

4-n-Butyl-2-methoxybenzoic acid (0.5 g; 2.9 mmol) and N-chloromorpholine(356 mg; 2.9 mmol) were treated in a similar manner to that described inPreparation 24 to give the title compound as a white soid (0.4 g).

PREPARATION 40 5-Bromo-4-iso-propyl-2-methoxybenzoic Acid

To a solution of 2-methoxy-4-iso-propyl benzoic acid (prepared in ananalogous manner to Preparation 37, 4-tert-butyl-2-methoxy benzoic acid)(7.0 g, 36.0 mmol) in chloroform (100 ml) was added bromine (1.86 ml) inchloroform (20 ml) dropwise. The reaction was stirred at roomtemperature overnight. Evaporation in vacuo afforded an oil (9.27 g).^(m) /_(z) (CI): 275, 273 (MH⁺ ; 70%).

PREPARATION 41 Methyl-5-bromo-4-iso-propyl-2-methoxy Benzoate

5-Bromo-4-iso-propyl-2-methoxybenzoic acid (9.268 g 34.0 mmol) wasdissolved in ethanol (250 ml) and conc. H₂ SO₄ (2 ml) added. The mixturewas refluxed for 5h and concentrated in vacuo. Residual material wastaken up into ethyl acethate and water, and the organic layer, dried(MgSO₄). Concentration in vacuo afforded an oil, which was purified byBiotage Column Chromatography on silica gel using 10% ether in hexane.An oil (5.5 g) was obtained.

PREPARATION 42 Methyl-4-iso-propyl-2-methoxy-5-trifluoromethyl Benzoate

A mixture of methyl-5-bromo-4-iso-propyl-2-methoxy benzoate (5.43 g,0.0189 mole), potassium trifluoroacethate (5.75 g, 0.0378 mole) andcopper (I) iodide (7.92 g, 0.042 mole) in DMF (100 ml) and toluene (30ml) were heated at 170° C. under argon to remove water (Dean-Stark Trap)and then heated to 155° C. overnight. On cooling, after concentration invacuo, the mixture was poured into ether (300 ml) and water (300 ml).After filtration through Kieselguhr, the organic layer was separated,washed with brine and dried (Na₂ SO₄). Concentration in vacuo afforded abrown yellow solid (4.85 g).

PREPARATION 43 4-iso-Propyl-2-methoxy-5-trifluoromethyl Benzoic Acid

Methyl-4-iso-propyl-2-methoxy-5-trifluoromethyl benzoate was dissolvedin methanol (100 ml), containing sodium hydroxide solution (2N, 100 ml).The mixture was allowed to stir at 25° C. overnight and then dil. HCladded until pH˜5. The solvent was then removed in vacuo and the residuetaken up in ethyl acethate and washed with brine. The organic layer wasdried over sodium sulfate and concentrated in vacuo to afford a crudesolid which as recrystallised with dichloromethane and hexane to give asolid (2.59 g).

PREPARATION 44 5-Pivaloyl-2-methoxy Benzoic Acid

5-Pivaloyl-2-methoxy benzyl alcohol (1.19 g, 5.35 mmol) was dissolved indioxane (20 ml). A solution of KOH (0.449 g, 8.025 mmol in water (5 ml)was added followed by KMnO₄ (1.69 g, 10.7 mmol). The mixture was allowedto stir at room temperature over the weekend. The solution was filteredthrough Celite and extracted with ether. The aqueous phase was acidifiedwith dil. HCl and extracted with ether (3×50 ml). The organic layer wasdried over magnesium sulphate and concentrated in vacuo to afford thetitle compound as a white solid (1.06 g).

PREPARATION 45 5-Pivaloyl-2-methoxy Benzyl Alcohol

5-Pivaloyl-2-methoxy benzyl TBDMS ether (1.8 g, 5.35 mmol) was dissolvedin methanol (30 ml); conc. HCl (20 drops) was added and the wholeallowed to stir at room temperature for 4h. Saturated NaHCO₃ solutionwas added and the mixture extracted with ether (2×100 ml). The organiclayer was dried over sodium sulfate and concentrated in vacuo to affordthe title compound as a colourless oil (1.19 g).

PREPARATION 46 5-Pivaloyl-2-methoxy Benzyl TBDMS Ether

n-Butyllithium (11.43 ml, 0.0183 mole, 1.6M in hexane) was slowly addedto a solution of 5-bromo-2-methoxy benzyl TBDMS ether in tetrahydrofuran(30 ml) over 45 mins at -31 78° C. The reaction mixture was maintainedunder argon at -78° C. for 1h. Then N,O-dimethylhydroxy dimethylhydroxypivaloyl amide (2.43 g, 0.0167 mole) was added dropwise with stirring at-78° C. The resulting mixture was allowed to stir at -78° C. for 2.5h,quenched with NH₄ Cl solution and allowed to warm to room temperature.The mixture was extracted with ether (2×50 ml), the combined organicswere dried (Na₂ SO₄) and concentrated in vacuo to give an oil. The oilwas purified by Biotage column chromatography on silica gel using 5%ether in hexane to afford the title compound as a colourless oil (2.95g).

PREPARATION 47 5-Bromo-2-methoxy Benzyl TBMS Ether

To a solution of 5-bromo-2-methoxy benzyl alcohol (20.87 g, 0.096 mole)in dichloromethane (300 ml), Et₃ N (20.90 ml, 0.15 mole) was addedtert-butyldimethylsilyl chloride (15.94 g, 0.10 mole) dropwise. Themixture was allowed to stir at room temperature overnight, then water(300 ml) was added. The organic layer was washed with brine, dried (Na₂SO₄) and evaporated to give a white solid. The title compound waspurified by dry flash column chromatography on silica gel using 20%ether in hexane to give a white solid (20.1 g).

PREPARATION 48 2,4-Dimethoxy-5-trifluoromethylbenzoic Acid

2,4-Dimethoxy-5-bromobenzoic acid methyl ester (1.5 g; 5.4 mmol) in DMF(25 ml) and toluene (8 ml) under argon was treated with potassiumtrifluoroacethate (1.53 g; 10.1 mmol) and copper (I) iodide (2.1 g, 10.9mmol). The mixture was heated to 170° C. with removal of water(Dean/Stark), and then at 155° C. overnight. The mixture was allowed tocool, poured into ether and water and filtered through Kieselguhr. Theorganic layer was dried (Na₂ SO₄) and concentrated in vacuo to give abrown solid. Chromatography on Kieselgel 60 with 1:1 ether/petrol gave awhite solid (1.03 g) which was hydrolised in 1:1 methanolic: aqueousNaOH (50 ml) at 50° C. Work-up gave the title compound as a white solid(1 g).

PREPARATION 49 2-Methoxy-4-(3-trifluoromethyl-3H-diazirinyl)benzoic Acid

The title compound was prepared from 4-bromo-2-methoxybenzyl alcoholusing a method similar to that described in Preparations 7 to 13.

PREPARATION 505-Iodo-2-methoxy-4-(3-trifluoromethyl-3H-diazirinyl)benzoic Acid

The benzoic acid of Preparation 49 (100 mg) in triflic acid (2 ml)containing N-iodosuccinimide (104 mg) was stirred at room temperatureovernight. The mixture was poured onto ice/water and extracted intoether. The combined organic extracts were washed with aqueous sodiumthiosulfate, dried (MgSO₄) and evaporation in vacuo gave the titlecompound as an off-white solid (115 mg; 78%).

PREPARATION 51 N-2-(4-Nitrophenyl)ethyl-trifluoroacetamide

A solution of trifluoroacetic anhydride (10.6 ml) in dichloromethane(100 ml) was added dropwise to a stirred solution of 2,6- lutidine(17.44 ml) and 4-nitrophenethylamine hydrochloride (15.2 g; 75 mmol) at0° C. The mixture was stirred at 25° C. overnight under argon and thenwashed with dilute citric acid (×2), brine and dried over Na₂ SO₄. Thematerial in the organic phase gave the title compound as a pale yellowsolid (19.04 g).

PREPARATION 52 7-Nitro-1,2,3,4-tetrahydro-2-trifluoroacetyl-isoquinoline

The nitro compound of Preparation 51 (2.26 g; 9.15 mmol) andparaformaldehyde (0.45 g; 14.4 mmol) in acetic acid (10 ml) and conc. H₂SO₄ (15 ml) were stirred at 25° C. for 20h according to the procedure ofG. E. Stokker., Tet. Lett., 1996, 37, 5453. Work up afforded the titlecompound as a white solid (2.17 g).

¹ H NMR (CDCl₃) δ: 3.10 (2H, m), 3.92 (2H, m), 4.85+4.92 (2H, 2×s), 7.38(1H, t), 8.10 (2H, m). ^(m) /_(z) (EI): 274 (M⁺)

PREPARATION 53 7-Nitro-1,2,3,4-tetrahydroisoquinoline

The trifluoroacetamide of Preparation 52 (17.22 g; 63 mmol) washydrolysed at room temperature using a solution of potassium carbonate(46.6 g) in 10% aqueous methanol (660 ml). Work-up with dichloromethanegave the title compound (11 g).

PREPARATION 54 2-Methyl-7-nitro-1,2,3,4-tetrahydroisoquinoline

The amine of Preparation 53 (2.08 g; 11.7 mmol) was treated with 88%formic acid (3.45 ml) and 37% aqueous formaldehyde (5.88 ml) at 80° C.for 2h according to the procedure of G. M. Carrera and D. S. Garvey, J.Het. Chem., 1992, 29, 847. Basification with 10% sodium hydroxidefollowed by work-up with ethyl acethate afforded an orange gum(2.3 g).Chromatography on Kiesegel 60 in 0-3% methanol-ethyl acethate gave thetitle compound as an orange solid (1.7 g).

^(m) /_(z) (CI): 193 (MH⁺)

PREPARATION 55 7-Amino-2-methyl-1,2,3,4-tetrahydroisoquinoline

The 7-nitro compound of Preparation 54 (0.25 g; 1.3 mmol) in methanol(40 ml) was hydrogenated over 10% palladium on carbon (100 mg) atatmospheric pressure overnight. The catalyst was removed by filtrationthrough a pad of Kieselguhr and evaporation in vacuo gave the titlecompound as a white solid (213 mg).

^(m) /_(z) (CI): 163 (MH⁺)

PREPARATION 567-Amino-2-(t-butyloxycarbonyl)-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared from the compound of Preparation 53using di t-butyl dicarbonate in 10% aqueous hydroxide in dioxan at 25°C. followed by catalytic hydrogenation according to the proceduresdescribed for Preparations 15 and 55.

PREPARATION 57 7-Amino-1,2,3,4-tetrahydro-2-trifluoroacetyl-isoquinoline

The 7-nitro compound of Preparation 52 (0.99 g; 3.6 mmol) in ethanol (50ml) was hydrogenated over 10% palladium on carbon (450 mg) atatmospheric pressure for 4h. The catalyst was removed by filtrationthrough a pad of Celite and evaporation in vacuo gave the title compoundas a white solid (840 mg).

¹ H NMR (250 MHz, CDCl₃) δ: 2.84 (2H, t), 3.23 (2H, br s), 3.82 (2H, m),4.66 (2H,d, restricted rothation around C-1), 6.47 (1H, m), 6.57 (1H,m), 6.96 (1H, m)

PREPARATION 58 2-Methyl-5-nitro-1,2,3,4-tetrahydroisoquinoline

5-Nitroisoquinoline was quaternized with methyl iodide and then reducedusing sodium borohydride according to the procedures of Preparations 1and 2 to give the title compound.

PREPARATION 59 7-Iodo-2-methyl-5-nitro-1,2,3,4-tetrahydroisoquinoline

The nitro compound of Preparation 58 (100 mg; 0.52 mmol) andN-iodosuccinimide (118 mg) in triflic acid (3 ml) was stirred at 25° C.overnight. The mixture was poured cautiously into saturated NaHCO₃ andthen extracted into ether (2×). The combined organic extracts werewashed with aqueous sodium thiosulfate, dried (MgSO₄) and evaporation invacuo gave a residue. Chromatography on Kieselgel 60 in 1%methanol-dichloromethane gave the title compound (101 mg; 61%).

^(m) /_(z) (API⁺): 319 (MH⁺ ; 100%).

PREPARATION 60 5-Amino-7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinoline

A solution of the nitro compound of Preparation 59 (101 mg) in ethanol(20 ml) at 50° C. was treated with a solution of tin (II) chloride (243mg) in conc. hydrochloric acid (1 ml). The resulthant yellow solutionwas basified with 10% aqueous sodium hydroxide and the product extractedinto dichloromethane. Flash chromatography on Kieselgel 60 (5%methanol-dichloromethane) gave the title compound (65 mg; 70%).

¹ H NMR (CDCl₃) δ: 2.40 (3H, s), 2.46 (2H, t), 2.68 (2H, t), 2.90-3.50(2H, br), 3.42 (2H, s), 6.75(1H, d, J=1.5 Hz), 6.81 (1H, d, J=1.5 Hz).^(m) /_(z) (API): 289(MH⁺ ; 100%).

PREPARATION 617-Amino-5-iodo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared from the nitro compound of Preparation52 using a procedure similar to that of Preparations 59 and 60.

PREPARATION 625-Amino-7-iodo-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared from5-nitro-1,2,3,4-tetrahydroisoquinoline using procedures similar to thoseoutlined in Preparations 51, 59 and 60.

PREPARATION 63 8-Fluoro-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared using a method similar to that describedby W. L. Mendelson et al; Tethrahedron Lett., 1980, 21, 1393.

PREPARATION 64 5-Nitro-8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline

The compound of Preparation 63 was nitrated using potassium nitrate andconc. sulfuric acid using sthandard conditions to give5-nitro-8-fluoro-1,2,3,4-tetrahydroisoquinoline. This was treated with88% formic acid and 37% aqueous formaldehyde at 80° C. for 2h accordingto the procedure of G. M. Carrera and D. S. Garvey, J. Het. Chem., 1992,29, 847 to give the title compound.

PREPARATION 65 5-Amino-8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline

The title compound was prepared by hydrogenation of5-nitro-8-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline (Preparation64) using a method similar to that of Preparation 55 with ethyl acethateas solvent.

^(m) /_(z) (API⁺): 181 (MH⁺ ; 80%)

EXAMPLE 1N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-chloro-2-methoxy-benzamideHydrochloride

4-Amino-5-chloro-2-methoxybenzoic acid (2.08 g, 11.1 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.77 g 9.24mmol) and 1-hydroxybenzotriazole (1.25 g, 9.24 mmol) were dissolved indry DMF (40 ml) and stirred at room temperature under argon for 0.5hbefore 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.5 g, 9.24mmol) was added. The mixture was then stirred for 18 h under argon atroom temperature. The DMF was removed in vacuo and the residue taken upinto ethyl acethate and washed with water, saturated aqueous sodiumbicarbonate and brine. The organic layer was dried over sodium sulfateand concentrated in vacuo to afford a yellow solid. This was then passedthrough a short pad of silica eluting with dichloromethane to afford awhite solid which was then taken up into methanol and treated withhydrogen chloride (1M in ether, 1 equivalent). The solvent was removedin vacuo and the residue recrystallised from methanol and ethyl acethateto afford the title compound as a white solid (0.775 g).

¹ H NMR(DMSO-d6) δ: 2.93 (3H, s), 3.10 (2H, s), 3.30 (2H, s), 3.90 (3H,s), 4.30-4.50 (2H, brs), 6.10 (2H, s), 6.60 (1H, s), 6.97 (1H, d, J=6Hz), 7.28 (1H, t, J=6 Hz), 7.80 (1H, s), 8.00 (1H, d, J=6 Hz), 9.63 (1H,s), 10.89 (1H, s).

EXAMPLE 2N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,4-dimethoxybenzamideHydrochloride

To a solution of 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.25g, 1.54 mmol) in ethyl acethate (5 ml) was added 2,4-dimethoxybenzoylchloride (0.263 g 1.54 mmol). The mixture was stirred under argon for 2h before the precipithate was filtered off and dried to afford the titlecompound as white solid.

¹ H NMR (DMSO-d6) δ: 2.90 (3H, s), 3.05(2H, br. s), 3.35(2H, s),3.85(3H,s), 4.03 (3H, s), 4.25-4.55(2H, m), 6.70 (1H, dd, J's=1,6 Hz), 6.75(1H,m), 7.00 (1H, d, J=6 Hz), 7.30 (1H, t, J=6 Hz), 7.95(2H, m), 9.75(1H,s), 11.25(1H, br. s); m/z (M+H)+327.

EXAMPLE 3N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxybenzamideHydrochloride

The title compound was prepared in an analogous fashion to Example 2from 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and2-methoxybenzoyl chloride.

¹ H NMR (DMSO-d6) δ: 2.90 (3H, s), 3.08 (2H, m), 3.38 (1H, m), 3.75(1H,m), 4.00 (3H, s), 4.30 (1H, m), 4.50 (1H, m), 7.05(1H, d, J=8 Hz), 7.11(1H, t, J=8 Hz), 7.23 (1H, d, J=8 Hz), 7.31 (1H, t, J=8 Hz), 7.55(1H, t,J=8 Hz), 7.85(2H, m), 9.85(1H, s), 10.95(1H, br, s); m/z (M+H)+297.

EXAMPLE 4N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and5-chloro-2-methoxybenzoic acid.

¹ H NMR (DMSO-d6) δ: 2.36 (3H, s), 2.67 (2H, m), 2.73 (2H, m), 3.51 (2H,s), 3.98 (3H, s), 6.92 (1H, d, J=6 Hz), 7.16 (1H, t, J=7 Hz), 7.28 (1H,d, J=8 Hz), 7.61 (1H, dd, J's=3,10 Hz), 7.71 (1H, d, J=8 Hz), 7.83 (1H,d, J=3 Hz), 9.79 (1H, s); m/z (M+H)+331.

EXAMPLE 5N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-chloro-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-chloro-2-methoxybenzoic acid.

¹ H NMR (DMSO-d6) δ: 2.40 (3H, s), 2.78 (4H, br. s), 3.60 (2H, br. s),4.02 (3H, s), 6.93 (1H, d, J=5 Hz), 7.18 (1H, dd, J's=1,5 Hz), 7.35(1H,d, J=1 Hz), 7.74 (1H,d, J=5 Hz), 7.89 (1H, d, J=5 Hz), 9.71 (1H, s); m/z(M+H)+331.

EXAMPLE 6N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-acetylamino-5-bromo-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-acetylamino-5-bromo-2-methoxybenzoic acid.

¹ H NMR (DMSO-d6) δ: 2.15(3H, s), 2.35(3H, s), 2.61-2.81 (4H, m), 3.50(2H, m) 3.98 (3H, s), 6.90 (1H, d, J=6 Hz), 7.15(1H, t, J=6 Hz), 7.72(1H, s) 7.78 (1H, d, J=8 Hz), 8.07 (1H, s), 9.22 (1H, s), 9.53 (1H, s);m/z (M+H)+432.

EXAMPLE 7N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-bromo-2-methoxybenzamide

To a solution of4-acetylamino-5-bromo-2-methoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide(0.888 g, 2 mmol) in ethanol (30 ml) and water (10 ml) was added 10%aqueous sodium hydroxide (1.25 ml). The mixture was heated at reflux for1.25h before pouring into water and extracting with chloroform. Theorganic layer was dried over sodium sulfate, concentrated in vacuo andthe residue recrystallised from ethyl acethate to afford the titlecompound as a brown solid (0.062 g).

¹ H NMR (DMSO-d6) δ: 2.34 (3H, s), 2.68 (4H, m), 3.45(2H, s), 3.95(3H,s), 6.08 (2H, s), 6.57 (1H, s), 6.80 (1H, d, J=6 Hz), 7.12 (1H, t, J=6Hz), 7.95(1H, d, J=6 Hz), 7.99 (1H, s), 9.60 (1H, s); m/z (M+H)+390.

EXAMPLE 8N-(2-Methyl-1,2,3,4-tetrahydroisoquinol-5-yl)-4-azido-5-iodo-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-azido-5-iodo-2-methoxybenzoic acid.

¹ H NMR (CDCl3) δ: 2.48 (3H, s), 2.75-2.85(4H, m), 3.62 (2H, s), 4.10(3H, s), 6.74 (1H, s), 6.87 (1H, d, J=7 Hz), 7.22 (1H, t, J=7 Hz), 8.08(1H, d, J=7 Hz), 8.69 (1H, s), 9.50 (1H, br. s); m/z (M+H)+464.

EXAMPLE 9 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-acetylamino-5-chloro-2-propoxy-benzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-acetylamino-5-chloro-2-propoxybenzoic acid.

¹ H NMR (DMSO-d6) δ: 0.96 (3H, t, J=6 Hz), 1.84 (2H, m), 2.18 (3H, s),2.37 (3H, s), 2.65(2H, m), 2.75(2H, m), 3.53 (2H, s), 4.14 (2H, t, J=6Hz), 6.92 (1H, d, J=6 Hz), 7.15(1H, t, J=6 Hz), 7.65(1H, d, J=6 Hz),7.85(1H, s), 7.90 (1H, s), 9.58 (1H, s), 9.64 (1H, s); m/z (M+H)+416.

EXAMPLE 10N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-chloro-2-propoxy-benzamide

4-Acethylamino-5-chloro-2-propoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide(0.877 g, 2 mmol) was added to a mixture of 10% sodium hydroxide (1.25ml) and water (5 ml) in ethanol (30 ml) and heated at reflux for 1.25h.The mixture was then cooled, poured into a large volume of water andextracted with chloroform. The organic layer was dried over sodiumsulfate, concentrated in vacuo and the residue recrystallised from ethylacethate to afford the title compound as a yellow crystalline solid (387mg).

¹ H NMR (DMSO-d6) δ: 0.98 (3H, t, J=6 Hz), 1.85(2H, m), 2.35(3H, s),2.64 (2H, m), 2.70 (2H, m), 3.50 (2H, s), 4.15(2H, t, J=6 Hz), 6.10 (2H,s), 6.60 (1H, s), 6.85(1H, d, J=6 Hz), 7.12 (1H, t, J=6 Hz), 7.80 (1H,s), 7.96 (1H, s), 9.42 (1H, s); m/z (M+H)+374.

EXAMPLE 11N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-acetylamino-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-acetylamino-2-methoxybenzoic acid.

¹ H NMR(DMSO-d6) δ: 2.08 (3H, s), 2.52 (3H, s), 2.87 (4H, br. s), 3.71(2H, br.s), 3.99 (3H, s), 6.90 (1H, d, J=8 Hz), 7.17 (1H, t, J=7 Hz),7.35(1H, d, J=8 Hz), 7.70 (1H, s), 7.91 (2H, m), 9.75(1H, s), 10.71 (1H,s); m/z (M+H)+354.

EXAMPLE 12N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-nitrobenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and5-chloro-2-methoxy-4-nitrobenzoic acid.

¹ H NMR (DMSO-d6) δ: 2.35(3H, s), 2.63 (2H, m), 2.77 (2H, m), 3.51 (2H,s), 3.99 (3H, s), 6.99 (1H, d, J=5 Hz), 7.17 (1H, t, J=5 Hz), 7.54 (1H,d, J=5 Hz), 7.91 (1H,s), 7.99 (1H, s), 9.77 (1H, s); m/z (M+H)+376.

EXAMPLE 13N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-iodo-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-amino-5-iodo-2-methoxybenzoic acid.

¹ H NMR (DMSO-d6) δ: 2.35(3H, s), 2.70 (4H, m), 3.50 (2H, s), 3.95(3H,s), 5.95 (2H, s), 6.55(1H, s), 6.82 (1H, d, J=6 Hz), 7.13 (1H, t, J=6Hz), 7.95(1H, d, J=6 Hz), 8.18 (1H, s), 9.58 (1H, s); m/z (M+H)+438.

EXAMPLE 14N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-benzyloxy-5-chloro-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-benzyloxy-5-chloro-2-methoxybenzoic acid.

¹ H NMR (DMSO-d6) δ: 2.35(3H, s), 2.68 (2H, m), 2.76 (2H, m), 3.49 (2H,s), 4.08 (3H, s), 5.39 (2H, s), 6.88 (1H, d, J=7 Hz), 7.09 (1H, s), 7.16(1H, t, J=7 Hz), 7.37-7.57 (5H, m), 7.85(1H, d, J=7 Hz), 7.95(1H, s),9.68 (1H, s); m/z (M+H)+437.

EXAMPLE 15N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4,5-dichloro-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4,5-dichloro-2-methoxybenzoic acid

¹ H NMR (DMSO-d6) δ: 2.34 (3H, s), 2.65(2H, m), 2.76 (2H, m), 3.50 (2H,s), 4.03 (3H, s), 6.92 (1H, d, J=7 Hz), 7.16 (1H, t, J=7 Hz), 7.55(1H,s), 7.67 (1H, d, J=8 Hz), 7.98 (1H, s), 9.70 (1H, s); m/z (M+H)+365.

EXAMPLE 16N-(2-Methyl-1,2;3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamide

5-Chloro-2,4-dimethoxybenzoic acid (0.245 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.186 g, 0.94 mmol) and1-hydroxybenzotriazole (0.144 g, 0.94 mmol) were dissolved in dry DMF(10 ml) and stirred at room temperature under argon for 25 mins before5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.153 g, 0.94 mmol) wasadded. The mixture was then stirred for 24h under argon at roomtemperature. The DMF was removed in vacuo and the residue taken up intoethyl acethate and washed with water. The organic layer was dried overmagnesium sulfate, concentrated in vacuo and the residue recrystallisedfrom ethyl acethate/hexane to afford the title compound as a solid(0.069 g).

¹ H NMR (DMSO-d6) δ: 2.34 (3H, s), 2.67 (2H, m), 2.75(2H, m), 3.49 (2H,s), 3.99 (3H, s), 4.10 (3H, s), 6.87 (1H, d, J=5 Hz), 6.95(1H, s)7.15(1H, t, J=5 Hz), 7.89 (1H, d, J=5 Hz), 7.94 (1H, s), 9.70 (1H, s);m/z (M+H)+361.

EXAMPLE 17N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2,4-dimethoxybenzamide

5-Bromo-2,4-dimethoxybenzoic acid (0.296 g, 1.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.186 g, 0.94 mmol) and1-hydroxybenzotriazole (0.144 g, 0.94 mmol) were dissolved in dry DMF(10 ml) and stirred at room temperature under argon for 25 mins before5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.153 g, 0.94 mmol) wasadded. The mixture was then stirred overnight under argon at roomtemperature. The DMF was removed in vacuo and the residue taken up intoethyl acethate and washed with water. The organic layer was dried overmagnesium sulfate, concentrated in vacuo and the residue recrystallisedfrom ethyl acethate/hexane to afford the title compound as a solid(0.106 g)

¹ H NMR (DMSO-d6) δ: 2.35(3H, s), 2.68 (2H, m), 2.75(2H, d, m), 3.49(2H, s), 3.99 (3H, s), 4.12 (3H, s), 6.89 (2H, m), 7.15(1H, t, J=7 Hz),7.85(1H, d, J=7 Hz), 8.09 (1H, s), 9.68 (1H, s); m/z (M+H)+405.

EXAMPLE 18N-(2-Methyl-1,2,3,4-tetrahydroisoquinol-5-yl)-5-[3-(trifluoromethyl)-3H-diazirin-3-yl]-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and5-[3-(trifluoromethyl)-3H-diazirin-3-yl]-2-methoxybenzoic acid.

¹ H NMR, (CDCl₃) δ: 2.40 (3H, s), 2.65-2.78 (4H, m), 3.54 (2H, s), 4.00(3H, s), 6.80 (1H, d, J=7 Hz), 7.02 (1H, d, J=7 Hz), 7.14 (1H, t, J=7Hz), 7.36 (1H, dd, J's=2,7 Hz), 7.98-8.12 (2H, m), 9.50 (1H, s); m/z(M+H)+405.

EXAMPLE 19N-(1,2,3,4-Tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamide

To a solution of5-chloro-2,4-dimethoxy-N-[2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yl]benzamide(1 g) in dichloromethane (30 ml) at 0° C. was added trifluoracetic acid(3 ml). The mixture was then stirred at room temperature for 3h beforepouring into saturated aqueous sodium bicarbonate (100 ml) andextracting with dichloromethane. The organic phase was dried over sodiumsulfate and concentrated in vacuo to afford the title compound as an offwhite solid (700 mg).

¹ H NMR (DMSO-d6) δ: 2.62 (2H, m), 3.06 (2H, m), 3.85(2H, s), 4.00 (3H,s), 4.10 (3H, s), 6.86 (1H, d, J=7 Hz), 6.96 (1H, s), 7.13 (1H, t, J=7Hz), 7.86 (1H, d, J=7 Hz), 7.94 (1H, s), 9.70 (1H, s); m/z (M+H)+347.

EXAMPLE 20N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-methylbenzamide

5-Chloro-2-methoxy-4-methylbenzoic acid (0.202 g, 1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.200 g, 1 mmol) and1-hydroxy-benzotriazole (0.155 g, 25 mmol) were dissolved in dry DMF (10ml) and stirred at room temperature under argon for 25 mins before5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.163 g, 1 mmol) wasadded. The mixture was then stirred for 24 under argon at roomtemperature. The DMF was removed in vacuo and the residue suspended inethyl acethate and washed with water. The insoluble white precipithatewas filtered off, washed with water then dried to afford the titlecompound (149 mg).

¹ H NMR (methanol-d4) δ: 2.48 (3H, s), 3.07 (3H, s), 3.16 (2H, m), 3.63(2H, m), 4.09 (3H, s), 4.46 (2H, s), 7.13 (1H, d, J=9 Hz), 7.22 (1H, s),7.38 (1H, t, J=9 Hz), 7.78 (1H, d, J=9 Hz), 7.98 (1H, s); m/z (M+H)+345.

EXAMPLE 21N-(2-n-Propyl-1,2;3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamideHydrochloride

The title compound was prepared in an analogous manner to Example 2 from5-amino-2-n-5propyl-1,2,3,4-tetrahydroisoquinoline and5-chloro-2,4-dimethoxybenzoyl chloride.

¹ H NMR (DMSO-d6) δ: 0.95(3H, t, J=7 Hz), 1.82 (2H, m), 3.10 (3H, m),3.35(1H, m), 3.50 (1H, m), 3.77 (1H, m), 4.00 (3H, s), 4.11 (3H, s),4.34 (1H, m), 4.54 (1H, m), 6.95(1H, s), 7.05(1H, d, J=6 Hz), 7.32 (1H,t, J=6 Hz), 7.89 (2H, m), 9.75(1H, s), 10.93 (1H, br. s); m/z (M+H)+389.

EXAMPLE 22N-(2-Ethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamideHydrochloride

The title compound was prepared in an analogous manner to Example 2 from5-amino-2-ethyl-1,2,3,4-tetrahydroisoquinoline and5-chloro-2,4-dimethoxybenzoyl chloride.

¹ H NMR (DMSO-d6) δ: 1.36 (3H, t, J=7 Hz), 3.09 (2H, m), 3.12-3.85(4H,m), 4.00 (3H, s), 4.10 (3H, s), 4.30 (1H, m), 4.55(1H, m), 6.94 (1H, s),7.06 (1H, d, J=6 Hz), 7.32 (1H, t, J=6 Hz), 7.89 (2H, m), 9.76 (1H, s),10.85(1H, br.s); m/z (M+H)+375.

EXAMPLE 23N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and5-chloro-4-ethoxy-2-methoxybenzoic acid.

¹ H NMR (DMSO-d6) δ: 1.42 (3H, t, J=6 Hz), 2.34 (3H, s), 2.70 (4H, m),3.50 (2H, s), 4.08 (3H, s), 4.28 (2H, m), 6.87 (1H, d, J=6 Hz), 6.93(1H, s), 7.15(1H, the J=6 Hz), 7.86 (1H, d, J=6 Hz), 7.94 (1H, s), 9.70(1H, s); m/z (M=H)+375.

EXAMPLE 24N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,5-dimethoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 2,5-dimethoxybenzoicacid.

¹ H NMR (DMSO-d6) δ: 2.94 (2H, m), 3.04 (3H, s), 3.34 (2H, m), 3.58 (2H,m), 3.77 (3H, s), 3.95(3H, s), 7.16 (2H, m), 7.35(1H, m), 7.40 (1H, d,J=4 Hz), 7.75(1H, d, J=9 Hz), 7.92 (1H, d, J=9 Hz), 10.00 (1H, s); m/z(M+H)+327.

EXAMPLE 25N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2-methoxy-4-methylbenzamide

5-Bromo-2-methoxy-4-methylbenzoic acid (0.245 g, 1 mmol),1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (0.200 g, 1mmol) and 1-hydroxy-benzotriazole (0.155 g, 1 mmol) were dissolved indry DMF (10 ml) and stirred at room temperature under argon for 25 minsbefore 5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.163 g, 1 mmol)was added. The mixture was then stirred for 24 under argon at roomtemperature. The DMF was removed in vacuo and the residue suspended inethyl acethate and washed with water. The insoluble white precipithatewas filtered off, washed with water then dried to afford the titlecompound (210 mg).

¹ H NMR (methanol-d4) δ: 2.49 (3H, s), 3.05(2H, m), 3.07 (3H, s),3.15(2H, m), 3.62 (2H, m), 4.08 (3H, s), 4.47 (2H, s), 7.13 (1H, d, J=8Hz), 7.22 (1H, s), 7.38 (1H, t, J=7 Hz), 7.77 (1H, d, J=8 Hz), 8.14 (1H,s); m/z (M+H)+389

EXAMPLE 26N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-dimethylsulfamoyl-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and5-dimethylsulfamoyl-2-methoxybenzoic acid.

¹ H NMR (DMSO-d6) δ: 2.36 (3H, s), 2.60 (6H, s), 2.65(2H, m), 2.79 (2H,m), 3.51 (2H, s), 4.08 (3H, s), 6.92 (1H, d, J=7 Hz), 7.17 (1H, t, J=7Hz), 7.48 (1H, d, J=7 Hz), 7.79 (1H, d, J=7 Hz), 7.90 (1H, dd, J's=1,7Hz), 8.15(1H, d, J=1 Hz), 9.74 (1H, s); m/z (M+H)+404.

EXAMPLE 27N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-benzoyl-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-benzoyl-2-methoxybenzoic acid.

¹ H NMR (CDCl₃) δ: 2.6 (3H, s), 2.70-2.87 (4H, m), 3.54 (2H, s), 4.06(3H, s), 6.70 (1H, d, J=7 Hz), 7.23 (1H, d, J=7 Hz), 7.62-7.30 (5H, m),7.68-7.83 (2H, m), 8.10 (1H, d, J=7 Hz), 8.32 (1H, d, J=7 Hz), 9.7 (1H,br s); m/z (M+H)+401.

EXAMPLE 28N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and5-benzoyl-2-methoxy-benzoic acid.

¹ H NMR (CDCl₃) δ: 2.50 (3H, s), 2.72-2.92(4H, m), 3.63 (2H, s), 4.16(3H, s), 6.87 (1H, d, J=7 Hz), 7.15-7.26 (2H, m), 7.45-7.65(3H, m),7,76-7.85(2H, m), 8.08-8.19 (2H, m), 8.75(1H, d, J=2 Hz), 9.60 (1H, brs); m/z (M+H)+401.

EXAMPLE 29N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-4-acetylamino-5-chloro-2-methoxybenzamide

To a cooled solution of 4-acetylamino-5-chloro-2-methoxybenzoylchloride, (prepared from 4-acetylamino-5-chloro-2-methoxybenzoic acid,3.19 g) in dichloromethane was added8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (2.1 g) andtriethylamine (4 ml). After stirring at room temperature for 2.5h, themixture was basified with 10% sodium hydroxide. The organic layer wasseparated, dried and concentrated in vacuo. The residue was purified bychromatography on alumina eluting with chloroform, and then crystallisedfrom ethyl acethate to give the title compound.

EXAMPLE 30N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-4-amino-5-chloro-2-metboxybenzamide

To a solution of4-acetylamino-5-chloro-2-methoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)benzamide(0.95 g) in ethanol (20 ml) and water (10 ml) was added sodium hydroxide(0.1 g) and the mixture was heated on a steam bath for 45 min. Thereaction was concentrated in vacuo and the residue partitioned betweenmethylene chloride and water. The organic phase was dried andconcentrated in vacuo. Purification by chromatography on alumina elutingwith chloroform followed by crystallisation from ethyl acethate affordedthe title compound (0.51 g) m.p.=192-193° C.

¹ H NMR δ: 2.50 (3H, s), 2.50-2.99 (4H, m), 3.51 (2H, s), 3.95(3H, s),4.48 (2H, br s), 6.31 (1H, s), 6.86-7.27 (2H, m), 7.90-8.00 (1H, m),8.17 (1H, s), 9.30 (1H, br s).

EXAMPLE 31N-(2,3-Dihydro-2-methyl-1H-isoindol-4-yl)-5-chloro-2,4-dimethoxybenzamideHydrochloride

A solution of freshly prepared 4-amino-2,3-dihydro-2-methyl-1H-isoindole(400 mg, 3.0 mmol) in dry ethyl acethate (40 ml) under argon was treateddropwise with a solution of 5-chloro-2,4-dimethoxybenzoyl chloride (700mg, 3.0 mmol) in a mixture of ethyl acethate (10 ml) and dichloromethane(10 ml). The reaction was stirred at room temperature for 6h and thenconcentrated in vacuo. The residue was triturated with diethylether/ethyl acethate and then crystallised twice from methanol/diethylether to give the title compound as a pale grey solid (0.11 g).

¹ H NMR (DMSO-d6) δ: 3.01 (3H, s), 4.02 (3H, s), 4.06 (3H, s), 4.4-4.8(4H, br m), 6.93 (1H, s), 7.26 (1H, d, J=8 Hz), 7.42 (1H, t, J=8 Hz),7.56 (1H, d, J=8 Hz), 7.82 (1H, s), 9.98 (1H, s), 11.88 (1H, br s); m/z(M+H)+347.

EXAMPLE 32N-(3-Methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-6-yl)-4-tert-butyl-2-methoxybenzamide,Hydrochloride

The title compound was prepared from6-amino-3-methyl-2,3,4,5-tetraydro-1H-3-benzazepine and4-tert-butyl-2-methoxybenzoic acid.

¹ H NMR (DMSO-d⁶) δ: 1.32 (9H, s), 2.79 (3H, s), 3.08 (5H, m), 3.33 (1H,m), 3.60 (2H, m), 3.96 (3H, s), 7.28 (5H, m), 7.65(1H, d, J=10 Hz), 9.84(1H, s), 10.82 (1H, br s). ^(m) /_(z) (CI): 367 (MH⁺)

EXAMPLE 33N-(1,2,3,4-Tetrahydroisoquinolin-6-yl)-4-t-butyl-2-methoxybenzamide,Trifluoroacethate

The title compound was prepared from amine Preparation 33 (190 mg; 0.77mmol) and 4-t-butyl-2-methoxybenzoic acid (174 mg; 0.84 mmol) accordingto the procedure of Example 1. The product (350 mg) in dichloromethane(20 ml) containing trifluoroacetic acid (1 ml) was kept at 25° C. for 18hr and evaporation in vacuo followed by crystallisation of the residuefrom ethyl acethate:ether gave the title compound as off-white crystals(295 mg), m.p. 207-211° C.

¹ H NMR (DMSO-d⁶) δ: 1.33 (9H, s), 3.00 (2H, t), 3.39 (2H, t), 3.94 (3H,s), 4.25(2H, s), 7.10 (2H, m), 7.18 (1H, d), 7.55(1H, dd), 7.60 (1H, d),7.69 (1H, s), 9.03 (2H, br), 10.05(1H, s); Found: M⁺ 338.1998 calc forC₂₁ H₂₆ N₂ O₂ 338.2010

EXAMPLE 34N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-t-butyl-2-methoxybenzamide,Trifluoroacethate

The compound of Example 33 (168 mg; 0.37 mmol) and paraformaldehyde (224mg; 7.4 mmol) in dry tetrahydrofuran (5 ml) was stirred at 25° C. underargon and treated with sodium borohydride (152 mg; 4 mmol) andtrifluoroacetic acid (2 ml) according to the procedure of G. W. Gribble,Synthesis 1987, 709. Work-up gave a yellow gum (62 mg).

¹ H NMR (CDCl₃) δ: 1.36 (9H, s), 2.50 (3H, s), 2.75(2H, t), 2.97 (2H,t), 3.63 (2H, s), 4.06 (3H, s), 7.00 (2H, d), 7.16 (1H, dd), 7.35(1H,dd), 7.56 (1H, br s), 8.20 (1H, d), 9.76 (1H, s).

Treatment with trifluoroacetic acid followed by crystallisation fromethyl acethate:ether gave the title compound as white crystals (64 mg),m.p. 205-8° C.; Found: M⁺ 352.21549 Calc for C₂₂ H₂₈ N₂ O₂ 352.21666.

EXAMPLE 35N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxybenzamideHydrochloride

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-tert-butyl-2-methoxybenzoic acid.

¹ H NMR (DMSO-d⁶) δ: 1.32 (9H, s), 2.91 (3H, s), 3.06 (2H, m), 3.35(1H,m), 3.70 (1H, m), 4.02 (3H, s), 4.45(2H, m), 7.04 (1H, d, J=10 Hz),7.15(2H, m), 7.31 (1H, m), 7.82 (1H, d, J=12 Hz), 7.90 (1H, d, J=12 Hz),9.83 (1H, s), 10.82 (1H, s). ^(m) /_(z) CI: 353 (MH⁺).

EXAMPLE 36N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-n-butyl-2-methoxy-5-chloro-benzamide,Hydrochloride

The title compound was prepared in a similar manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-n-butyl-2-methoxy-5-chlorobenzoic acid.

¹ H NMR (DMSO-d⁶) δ: 0.93 (3H, m), 1.38 (2H, m), 1.58 (2H, m), 2.63 (2H,m), 2.90 (3H, s), 3.07 (2H, m), 3.35(1H, m), 3.70 (1H, m), 4.00 (3H, s),4.34 (1H, m), 4.48 (1H, m), 7.06 (1H, d, J=12 Hz), 7.23 (1H, s), 7.33(1H, m), 7.80 (2H, m), 9.83 (1H, s), 11.90 (1H, br s). ^(m) /_(z) (CI):387 (MH⁺)

EXAMPLE 37N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxy-5-chloroBenzamide, Hydrochloride

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-ethyl-2-methoxy-5-chlorobenzoic acid.

¹ H NMR (DMSO d⁶)δ: 1.24 (3H, m), 2.77 (2H, m), 2.91 (3H, s), 3.15(2H,m), 3.35(1H, m), 3.65(1H, m), 4.02 (3H, s), 4.40 (2H, m), 7.07 (1H, d,J=9 Hz), 7.26 (1H, s), 7.34 (1H, m), 7.77 (2H, m), 9.85(1H, s), 10.72(1H, br s) ^(m) /_(z) (CI): 359 (MH⁺).

EXAMPLE 38N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxy-5-chloro-benzamide,Hydrochloride

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-tert-butyl-2-methoxy-5-chlorobenzoic acid.

¹ H NMR (DMSO-d⁶) δ: 1.49 (9H, s), 2.91 (3H, s), 3.05(2H, m), 3.18 (2H,s), 3.35(1H, m), 4.03 (3H, s), 4.42 (1H, m), 7.08 (1H, d, J=8 Hz), 7.20(1H, s), 7.33 (1H, m), 7.79 (2H, m), 9.82 (1H, s), 10.66 (1H, br s).^(m) /_(z) (CI): 387 (MH⁺, 90%)

EXAMPLE 39N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-phenylbenzamide,Hydrochloride

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydoisoquinoline and2-methoxy-4-phenylbenzoic acid.

¹ H NMR (DMSO-d⁶)δ: 2.94 (3H, d), 3.11 (2H, m), 3.40 (1H, m), 3.78 (1H,m), 4.14 (3H, s), 4.35(1H, m), 4.55(1H, m), 7.08 (1H, d, J=9 Hz),7.35(1H, m), 7.50 (5H, m), 7.81 (2H, m), 7.89 (1H, d), 7.99 (1H, m),9.92 (1H, s), 10.80 (1H, br s). ^(m) /_(z) (CI): 373 (MH⁺, 100%).

EXAMPLE 40N-(1,2,3,4-Tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxybenzamideHydrochloride

The title compound was prepared in an analogous manner to Example 19.

¹ H NMR (DMSO-d⁶)δ: 1.31 (9H, s), 2.97 (2H, m), 3.37 (2H, m), 3.44 (2H,m), 4.06 (3H, s), 4.31 (2H, m), 7.08 (1H, d, J=9 Hz), 7.16 (2H, m), 7.28(1H, m), 7.84 (2H, m), 9.55(2H, br s), 9.83 (1H, s). ^(m) /_(z) (CI):339 (MH⁺ ; 80%).

EXAMPLE 41N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5yl)-4-iso-propyl-2-methoxybenzamide,Hydrochloride

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-iso-propyl-2-methoxybenzoic acid.

¹ H NMR (DMSO-d⁶)δ: 1.26 (6H, d), 2.92 (3H, s), 2.99 (1H, m), 3.09 (1H,m), 3.39 (1H, m), 3.73 (1H, m), 4.02 (3H, s), 4.33 (1H, m), 4.50 (1H,m), 7.03 (2H, m), 7.10 (1H, s), 7.31 (1H, m), 7.83 (2H, m), 9.83 (1H,s), 10.97 (1H, br s). ^(m) /_(z) (CI): 339 (MH⁺).

EXAMPLE 42N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-iso-propyl-2-methoxybenzamide,hydrochloride

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and5-chloro-4-iso-propyl-2-methoxybenzoic acid.

¹ H NMR (DMSO-d⁶) δ: 1.28 (6H, d), 2.91 (3H, m), 3.07 (2H, m), 3.33 (1H,m), 3.70 (1H, m), 4.03 (3H, s), 4.30 (1H, m), 4.52 (1H, m), 7.06 (1H, d,J=9 Hz), 7.16 (1H, s), 7.32 (1H, m), 7.76 (2H, m), 9.86 (1H, s), 10.68(1H, br s). ^(m) /_(zn) (CI): 373 (MH⁺ ; 90%).

EXAMPLE 43N-(1,2,3,4-Tetrahydroisoquinolin-5-yl)-5-chloro-4-tert-butyl-2-methoxybenzamide,Hydrochloride

The title compound was prepared in an analogous manner to Examples 19,20.

¹ H NMR (DMSO-d⁶) δ: 1.50 (9H, s), 2.95(2H, m), 3.42 (2H, m), 4.05(3H,s), 4.30 (2H, m), 7.10 (1H, d), 7.20 (1H, s), 7.30 (1H, m), 7.76 (2H,m), 9.50 (2H, br s), 9.81 (1H, s). ^(m) /_(z) (CI): 373 (MH+; 100%)

EXAMPLE 44N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxybenzamide,Hydrochloride

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and4-ethyl-2-methoxybenzoic acid.

¹ H NMR (DMSO-d⁶) δ: 1.23 (3H, t), 2.68 (2H, q), 2.91 (3H, s), 3.06 (2H,m), 3.35(1H, m), 3.71 (1H, m), 4.00 (3H, s), 4.40 (2H, m), 7.0 (2H, m),7.10 (1H, s), 7.30 (1H, m), 7.87 (2H, m), 9.80 (1H, s), 10.83 (1H, s).^(m) /_(z) (CI): 325(MH⁺ ; 100%).

EXAMPLE 45N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-iso-propoxy-2-methoxybenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶) δ: 1.36 (6H, d), 2.92 (3H, m), 3.05(2H, m), 3.49 (1H,m), 3.77 (1H, m), 4.06 (3H, s), 4.33 (1H, m), 4.55(1H, m), 4.93 (1H, m),6.91 (1H, s), 7.05(1H, d), J=9 Hz), 7.31 (1H, m), 7.84 (1H, d, J=10 Hz),8.02 (1H, s), 9.76 (1H, s), 10.57 (1H, br s). ^(m) /_(z) (CI): 435(MH⁺)

EXAMPLE 46N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propyl-5-trifluoromethyl-2-methoxybenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶) δ: 1.30 (6H, d), 2.90 (3H, s), 3.05(2H, m), 3.30 (1H,m), 3.50 (2H, m), 4.07 (3H, s), 4.39 (2H, m), 7.06 (1H, d, J=9 Hz), 7.31(2H, m), 7.74 (1H, d, J=10 Hz), 8.02 (1H, s), 9.86 (1H, s), 11.00 (1H,br s). ^(m) /_(z) (CI): 407 (MH⁺ ; 90%).

EXAMPLE 47N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propoxy-2-methoxy-5-trifluoromethyl-benzamide,Hydrochloride

¹ H NMR (DMSO-d⁶) δ: 1.33 (6H, d), 2.91 (3H, s), 3.06 (2H, m), 3.35(1H,m), 3.69 (1H, m), 4.11 (3H, s), 4.40 (2H, m), 5.06 (1H, m), 7.04 (2H,m), 7.31 (1H, m), 7.82 (1H, d, J=10 Hz), 8.10 (1H, s), 9.75(1H, s),11.00 (1H, br s). ^(m) /_(z) (CI): 423 (MH⁺ ; 100%).

EXAMPLE 48N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-iso-propyl-2-methoxybenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶)δ: 1.22 (6H, d), 2.90 (3H, s), 3.06 (2H, m), 3.33 (3H,m), 4.03 (3H, s), 4.43 (2H, m), 7.05(1H, d, J=8 Hz), 7.17 (1H, s), 7.31(1H, m), 7.70 (1H, d, J=10 Hz), 7.94 (1H, s), 9.82 (1H, s), 10.94 (1H,br s). ^(m) /_(z) (CI): 419 (MH⁺)

EXAMPLE 49 N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)5-iso-butyroyl-2-methoxy-benzamide Hydrochloride

The title compound was prepared in a similar manner to that of Example50.

¹ H NMR (DMSO-d⁶)δ: 1.06 (6H, d), 2.84 (3H, s), 3.04 (2H, m), 3.31 (1H,m), 3.62 (2H, m), 3.97 (3H, s), 4.37 (2H, m), 7.02 (1H, d, J=10 Hz),7.30 (2H, m), 7.66 (1H, d, J=10 Hz), 8.12 (1H, dd, J=12, 3 Hz), 8.30(1H, d, J=3.3 Hz), 9.80 (1H, s), 10.91 (1H, br s). ^(m) /_(z) (CI): 367(MH⁺)

EXAMPLE 50N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-pivaloyl-2-methoxybenzamide,Hydrochloride

The title compound was prepared in an analogous manner to Example 1 from5-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline and 5-pivaloyl-2-methoxybenzoic acid.

¹ H NMR (DMSO-d⁶)δ: 1.40 (9H, s), 2.95(3H, s), 3.13 (2H, m), 3.35(2H,m), 4.10 (3H, s), 4.47 (2H, m), 7.14 (1H, d, J=10 Hz), 7.39 (2H, m),7.80 (1H, d, J=10 Hz), 8.14 (1H, d, J=12 Hz), 8.54 (1H, s), 9.93 (1H,s), 10.65(1H, br s). ^(m) /_(z) (CI): 381 (MH⁺)

EXAMPLE 51N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chloro-2-methoxy-4-iso-propoxybenzamide,Trifluoroacethate

m.p. 164-9° C.

Free base: ¹ H NMR (CDCl₃)δ: 1.44 (6H, d), 2.46 (3H, s), 2.70 (2H, t),2.91 (2H, t), 3.60 (2H, s), 4.04 (3H, s), 4.66 (1H, m), 6.56 (1H, s),7.08 (1H, d), 7.28 (1H, dd), 7.46 (1H, d), 8.27 (1H, s), 9.53 (1H, s).^(m) /_(z) (CI): 389 (MH⁺ ; 50%).

EXAMPLE 52N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-bromo-2,4-dimethoxybenzamide,Hydrochloride Salt

¹ H NMR (250 MHz, CDCl₃ +CD₃ OD) δ: 2.89-3.19(4H, m and overlapping s at2.98 and HOD signal), 3.27 (1H, m), 3.46 (1H, m, overlapping with CHD₂OD signal), 3.70 (1H, m), 4.00 (3H, s), 4.11 (4H, overlapping s and d),4.58 (1H, br d), 6.54 (1H, s), 7.18 (1H, d), 7.38 (1H, d), 7.61 (1H, brs), 8.36 (1H, s), 9.69 (partially exchanged 1H, br s).

EXAMPLE 53N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-tert-butyl-2-methoxybenzamide

¹ H NMR (250 MHz, CDCl₃) δ: 1.35(9H, s), 2.46 (3H, s), 2.68 (2H, t),2.89 (2H, s), 3.59 (2H, s), 4.06 (3H, s), 7.01 (1H, d), 7.07 (1H, d),7.15(1H, dd), 7.31 (1H, dd), 7.50 (1H, d), 8.19 (1H, d), 9.74 (1H, br s)

EXAMPLE 54N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-methyl-5-trifluoromethylbenzamide

¹ H NMR (250 MHz, CDCl₃) δ: 2.47 (3H, s), 2.54 (3H, s), 2.70 (2H, t),2.91 (2H, t), 3.60 (2H, s), 4.10 (3H, s), 6.91 (1H, s), 7.09 (1H, d),7.30 (1H, dd), 7.48 (1H, d), 8.54 (1H, s), 9.55(1H, br s).

EXAMPLE 55N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxybenzamide,Hydrochloride Salt

¹ H NMR (250 MHz, CD₃ OD)δ: 3.00-3.53 (6H, m and overlapping s at 3.07and CHD₂ OD signal), 3.69-3.86 (1H, br m), 4.02 (3H, s), 4.36.(1H, d),4.57 (1H, d), 7.10 (1H, t), 7.20 (1H, d), 7.28 (1H, d), 7.48-7.60 (2H,overlapping signals), 7.73 (1H, s), 7.88 (1H, dd).

EXAMPLE 56N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,4-dimethoxybenzamide,Hydrochloride Salt

¹ H NMR (200 MHz, CD₃ OD)δ: 2.90-3.60 (6H, m overlapping with s at 3.09and CHD₂ OD signal), 3.60-3.95(4H, m overlapping with s at 3.91), 4.08(3H, s), 4.38 (1H, d), 4.60 (1H, d), 6.67-6.78 (2H, m, overlappingsignals), 7.30 (1H, d), 7.53 (1H, dd), 7.73 (1H, s), 7.99 (1H, d).

EXAMPLE 57N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chloro-2-methoxybenzamide

¹ H NMR (250 MHz, CDCl₃)δ: 2.46 (3H, s), 2.69 (2H, t), 2.89 (2H, t),3.60 (2H, s), 4.04 (3H, s), 6.97 (1H, d), 7.09 (1H, d), 7.30 (1H, dd),7.39-7.49 (2H, m, overlapping signals), 8.24 (1H, d), 9.65(1H, br s).

EXAMPLE 58N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propoxy-2-methoxybenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶) δ: 1.31 (6H, d, J=7 Hz), 3.42 (3H, s), 3.04 (2H, m),3.29-3.78 (2H, br m), 4.02 (3H, s), 4.24-4.56 (2H, m), 4.78 (1H, m),6.35(1H, m), 6.70 (2H, m), 7.02 (1H, m), 7.32 (1H, t, J=6 Hz), 7.95(2H,m), 9.73 (1H, s), 10.83 (1H, br s). ^(m) /_(z) (CI): 355(MH⁺)

EXAMPLE 59N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-dimethylsulfamoyl-2,4-dimethoxybenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶)δ: 2.72 (6H, s), 2.91 (2H, m), 3.05(2H, m), 3.38 (1H,m), 3.72 (1H, m), 4.05(3H, s), 4.15(3H, s), 4.35(1H, m), 4.56 (1H, m),7.95(1H, s), 7.06 (1H, d, J=6 Hz), 7.33 (1H, t, J=6 Hz), 7.80 (1H, d,J=6 Hz), 8.28 (1H, s), 9.72 (1H, s), 10.82 (1H, s).

EXAMPLE 60N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-iso-propylsulfonylbenzamide,Hydrochloride

¹ H NMR (DMSO d⁶)δ: 1.18 (6H, d, J=6 Hz), 2.90 (3H, s), 3.11 (2H, m),3.25-3.42 (2H, m), 3.70 (1H, m), 4.06 (3H, s), 4.34 (1H, m), 4.51 (1H,m), 7.08 (1H, d, J=6 Hz), 7.34 (1H, d, J=6 Hz), 7.47 (1H, d, J=6 Hz),8.00 (1H, d, J=6 Hz), 8.15(1H, s), 9.95(1H, s), 11.22 (1H, br s). ^(m)/_(z) (CI): 403 (MH⁺)

EXAMPLE 61N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-phenylbenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶)δ: 2.93 (3H, d), 3.10 (2H, br m), 3.35(1H, br m), 3.70(1H, br, overlapped), 4.04 (3H, s), 4.33 (1H, dd), 4.55(1H, d), 7.10(1H, d), 7.25(1H, s), 7.36 (1H, t), 7.55(5H, br s), 7.78 (1H, d), 7.93(1H, s). ^(m) /_(z) (CI): 407 (MH⁺, 100%).

EXAMPLE 62N-(1,2,3,4-Tetrahydroisoquinolin-5-yl)-5-bromo-2,4-dimethoxybenzamide,Trifluoroacethate

¹ H NMR (400 MHz, CDCl₃ +MeOH-d⁴) δ: 2.99 (2H, t, overlapping HOD), 3.48(2H, t), 4.00 (3H, s), 4.11 (3H, s), 4.34 (2H, s), 6.58 (1H, s), 7.02(1H, d), 7.27-7.36 (1H, m, overlapping CHCl₃), 7.75(1H, d), 8.38 (1H,s).

EXAMPLE 63N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-n-propylsulfonylbenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶)δ: 0.92 (3H, t, J=8 Hz), 1.56 (2H, m), 2.90 (3H, s),3.09 (2H, m), 3.36 (3H, m), 3.73 (1H, m), 4.02 (3H, s), 4.33 (1H, m),4.52 (1H, m), 7.09 (1H, d, J=7 Hz), 7.32 (1H, t, J=7 Hz), 7.47 (1H, d, J=8 Hz), 7.67 (1H, d, J=8 Hz), 8.03 (.H, dd, J=7, 1 Hz), 8.20 (1H, d, J=1Hz), 9.92 (1H, s), 11.0 (1H, br s). ^(m) /_(z) (CI): 403 (MH⁺).

EXAMPLE 64N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,4-dimethoxy-5-trifluoromethylbenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶)δ: 2.41 (3H, s), 3.04 (2H, m), 3.30-3.78 (2H, m), 4.03(3H, s), 4.13 (3H, s), 4.40 (2H, m), 7.05(2H, m), 7.32 (1H, t, J=6 Hz),7.85(1H, d, J=6 Hz), 8.12 (1H, s), 9.72 (1H, s), 11.32 (1H, br s). ^(m)/_(z) (CI): 395(MH⁺)

EXAMPLE 65N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-methyl-5-trifluoromethylbenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶)δ: 2.94 (3H, s), 3.08 (2H, m), 3.42 (1H, m), 3.70 (1H,m), 4.06 (3H, s), 4.40 (2H, m), 7.09 (1H, d, J=6 Hz), 7.34 (2H, m),7.75(1H, d, J=6 Hz), 8.08 (1H, s), 9.82 (1H, s), 10.83 (1H, s). ^(m)/_(z) (CI): 379 (MH⁺)

EXAMPLE 66N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-acetyl-2,4-dimethoxybenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶)δ: 2.48 (3H, s); 2.58 (3H, s), 2.92 (2H, m), 3.02 (2H,m), 3.38 (2H, m), 4.06 (3H, s), 4.12 (3H, s), 7.06 (1H, d, J=8 Hz), 7.33(.H, t, J=8 Hz), 7.78 (1H, d, J=8 Hz), 8.28 (1H, s), 9.70 (1H, s). ^(m)/_(z) (CI): 369 (MH⁺ ; 100%).

EXAMPLE 67N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-ethyl-2-methoxybenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶)δ: 1.21 (3H, t, J=8 Hz), 2.50 (3H, s), 2.78 (2H, q, J=8Hz), 2.92 (4H, m), 3.05(2H, m), 4.00 (3H, s), 7.06 (1H, d, J=7 Hz),7.25(1H, s), 7.32 (1H, t, J=7 Hz), 7.74 (1H, d, J=7 Hz), 7.93 (1H, s),9.82 (1H, s), 10.40 (1H, br s). ^(m) /_(z) (CI): 405, 403 (MH⁺, 100%).

EXAMPLE 68N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxy-5-trifluoromethylbenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶)δ: 1.40 (3H, t, J=8 Hz), 2.94 (2H, m), 2.99 (3H, s),3.17 (2H, m), 3.45(3H, s), 3.75(1H, m), 4.11 (1H, m), 4.24 (3H, s), 4.50(2H, m), 7.17 (1H, d, J=7 Hz), 7.42 (2H, m), 7.86 (1H, d, J=7 Hz), 8.16(1H, s), 9.94 (1H, s), 11.26 (1H, br s) ^(m) /_(z) (CI): 393 (MH⁺)

EXAMPLE 69N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-n-butoxy-5-chloro-2-methoxybenzamide,Hydrochloride

¹ H NMR (DMSO-d⁶)δ: 0.98 (3H, t, J=6 Hz), 1.48 (2H, m), 1.29 (2H, m),2.89 (3H, s), 3.06 (2H, m), 3.70 (1H, m), 4.10 (3H, s), 4.24 (2H, t, J=6Hz), 4.48 (1H, m), 6.95(1H, s), 7.04 (1H, d, J=6 Hz), 7.32 (1H, t, J=6Hz), 7.79 (2H, m), 9.75(1H, s), 11.20 (1H, br s). ^(m) /_(z) (CI): 403(MH⁺)

EXAMPLE 70N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-iso-propyloxy-5-acetyl-benzamide,Hydrochloride

¹ H NMR (free base; CDCl₃) δ: 1.39 (6H, d, J=7 Hz), 2.48 (3H, s), 2.59(3H, s), 2.79 (4H, m), 3.61 (2H, s), 4.09 (3H, s), 4.76 (1H, s), 6.51(1H, s), 6.84 (1H, d, J=8 Hz), 7.20 (1H, t, J=8 Hz), 8.13 (1H, d, J=8Hz), 8.73 (1H, s), 9.36 (1H, br s). ^(m) /_(z) (CI): 397 (MH⁺ ; 100%).

EXAMPLE 71N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-iso-propoxybenzamide,Hydrochloride

¹ H NMR (DMSO d⁶)δ: 1.37 (6H, d, J=6 Hz), 2.92 (3H, s), 3.05(2H, m),3.37 (1H, m), 3.73 (1H, m), 4.08 (3H, s), 4.32 (1H, m), 4.51 (1H, m),4.96 (1H, m), 6.95(1H, s), 7.06 (1H, d, J=6 Hz), 7.32 (1H, t, J=6 Hz),7.89 (2H, m), 9.27 (1H, s), 11.20 (1H, br s). ^(m) /_(z) (CI): 389 (MH⁺,80%)

EXAMPLE 72N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-iodo-4-trifluoromethyldiazirinylBenzamide

¹ H NMR (200 MHz, CDCl₃)δ: 2.48 (3H, s), 2.81 (4H, br s), 3.64 (2H, brs), 4.13 (3H, s), 6.88 (1H, d), 7.20 (1H, t), 7.23 (1H, s), 8.05(1H, d),8.77 (1H, s), 9.50 (1H, br s). ^(m) /_(z) (CI): 531 (MH⁺)

EXAMPLE 73N-(1,2,3,4-Tetrahydroisoquinolin-5-yl)-4-azido-5-iodo-2-methoxybenzamide,Trifluoroacethate

¹ H NMR (200 MHz, MeOD-d⁴)δ: 3.13 (2H, t), 3.53 (2H, t), 4.14 (3H, s),4.38 (2H, s), 6.89 (1H, s), 7.12 (1H, d), 7.37 (1H, t), 7.65(1H, s),7.70 (1H, d), 8.48 (1H, s). ^(m) /_(z) (CI): 450 (MH⁺ ; 100%).

EXAMPLE 74N-(1,2,3,4-Tetrahydroisoquinolin-5-yl)-5-iodo-2-methoxy-4-trifluoromethyldiazirinylbenzamide,Trifluoroacethate

¹ H NMR(250 MHz, MeOD-d⁴)δ: 3.11 (2H,t), 3.59 (2H, t), 4.14 (3H, s),4.40(2H, s), 7.18 (1H, d), 7.38 (1H, t), 7.55(1H, s), 7.69 (1 H, d), 8.42(1H, s). ^(m) /_(z) (CI): 517 (MH⁺ ; 80%).

EXAMPLE 75N-(7-Iodo-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide

¹ H NMR (CDCl₃)δ: 2.41 (3H, s), 2.70 (4H, s), 3.50 (2H, s), 4.10 (3H,s), 7.12-7.23 (2H, m), 7.41-7.68 (3H, m), 7.74-7.85(2H, m), 8.12 (1H,dd), 8.55(1H, s), 8.72 (1H, d), 9.61 (1H, br s).

EXAMPLE 76N-(7-Iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamide,Trifluoroacethate

¹ H NMR (250 MHz, DMSO-d⁶)δ: 2.92 (2H, br s), 3.46 (2H, br s), 4.08 (3H,s), 4.32 (2H, br s), 7.42 (1H, d), 7.54-7.76 (6H, m), 7.98 (1H, d), 8.10(1H, s), 8.21 (1H, s), 9.26 (2H, br s), 9.98 (1H, s). ^(m) /_(z) (CI,API-): 511 (M⁺ -H).

EXAMPLE 77N-(5-Iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamide,Trifluoroacethate

¹ H NMR (250 MHz, DMSO-d⁶)δ: 2.82 (2H, t), 3.44 (2H, br s), 4.01 (3H,s), 4.31 (2H, br s), 7.38 (1H, d), 7.57-7.72 (6H, m), 7.95-8.00 (2H, m),8.22 (1H, s), 9.15(2H, br s), 10.35(1H, s). ^(m) /_(z) (CI): 513 (MH⁺ ;100%).

EXAMPLE 78N-(5-Iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-trifluoromethyldiazirinylbenzamide,Trifluoroacethate

¹ H NMR (250 MHz, DMSO-d⁶)δ: 2.82 (2H, br s), 3.50 (2H, br s), 3.93 (3H,s), 4.30 (2H, br s), 7.24 (1H, d), 7.34 (1H, d), 7.41-7.48 (1H, m),7.64-7.78 (2H, m), 8.22 (1H, s), 9.20 (2H, br s), 10.25(1H, s). ^(m)/_(z) (CI): 517 (MH⁺ ; 100%).

EXAMPLE 79N-(5-Iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromethyldiazirinylbenzamide,Trifluoroacethate

¹ H NMR (250 MHz, DMSO-d⁶)δ: 2.82 (2H, br s), 3.43 (2H, br s), 3.91 (3H,s), 4.30 (2H, br s), 6.86 (1H, s), 7.12 (1H, d), 7.68-7.71 (2H, m), 8.20(1H, s), 9.18 (2H, br s), 10.33 (1H, s).

EXAMPLE 80N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoroacetylBenzamide

¹ H NMR (DMSO-d⁶)δ: 2.54 (3H, s), 2.82 (4H, s), 3.73 (2H, s), 4.29 (3H,s), 6.91 (1H, d), 7.18 (1H, t), 7.31 (1H, d), 8.04 (1H, d), 8.41 (1H,d), 8.96 (1H, s), 9.61 (1H, br s). ^(m) /_(z) (CI): 393 (MH⁺)

EXAMPLE 81N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-trifluoromethyldiazirinylBenzamide

¹ H NMR (DMSO-d⁶)δ: 2.52 (3H, s), 2.83 (4H, s), 3.69 (2H, s), 4.09 (3H,s), 6.78 (1H, s), 6.86 (1H, d), 6.97 (1H, d), 7.21(1H, t), 8.08 (1H, d),8.37 (1H, d), 9.56 (1H, br s).

EXAMPLE 82N-(1,2,3,4-Tetrahydroisoquinolin-7-yl)-5-iodo-2-methoxy-4-trifluoromethyldiazirinylbenzamide,Trifluoroacethate ^(m) /_(z) (CI): 517 (MH⁺ ; 100%). EXAMPLE 83N-(1,2,3,4-Tetrahydroisoquinolin-5-yl)-5-(4-iodobenzoyl)-2-methoxybenzamide,Trifluoroacethate

¹ H NMR (250 MHz, DMSO-d⁶)δ: 2.98 (2H, t), 3.42 (2H, br s), 4.08 (3H,s), 4.35(2H, br s), 7.12 (1H, d), 7.33(1H, t), 7.41 (1H, d), 7.52 (2H,d), 7.65(1H, d), 7.95-8.03 (3H, m), 8.16 (1H, d), 9.09 (2H, br s), 9.90(1H, s).

EXAMPLE 84N-(7-Iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoromethydiazirinylBenzamide, Trifluoroacethate

¹ H NMR (250 MHz, DMSO-d⁶)δ: 2.90 (2H, br s), 3.45(2H, br s), 4.01 (3H,s), 4.32 (2H, br s), 7.38 (1H, d), 7.50-7.54 (2H, m), 7.70 (1H, s), 8.11(1H, s), 9.28 (2H, br s), 9.91 (1H, s). ^(m) /_(z) (CI): 517 (MH⁺ ;100%).

EXAMPLE 85N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-2-methoxybenzamide

¹ H NMR (CDCl₃)δ: 2.47 (3H, s), 2.70 (2H, t), 2.90 (2H, t), 3.61 (2H,s), 4.06 (3H, s), 7.03 (1H, s), 7.11 (1H, t), 7.47 (1H, s), 8.22 (1H, d,J=7 Hz), 9.55(1H, br s). ^(m) /_(z) (API⁺): MH⁺ at 333 (37%) and 331(100%)

EXAMPLE 86N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-methylthiobenzamide

¹ H NMR (CDCl₃) δ: 2.53 (3H, s); 2.54 (3H, s), 2.69 (2H, t), 2.88 (2H,t), 3.60 (2H, s), 4.05(3H, s), 6.86 (1H, d), 6.95(1H, dd), 7.08 (1H, d,J=7 Hz), 7.28 (1H, dd), 7.49 (1H, d), 8.22 (1H, d, J=7 Hz), 9.64 (1H, brs). ^(m) /_(z) (API⁺): 343 (MH⁺ ; 100%).

EXAMPLE 87N-(8-Fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-t-butyl-2-methoxybenzamide

^(m) /_(z) (API⁺): 371 (MH⁺ ; 80%).

EXAMPLE 88N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iso-butyroyl-4-iso-propoxy-2-methoxybenzamide

¹ H NMR (CDCl₃) δ: 1.15(6H, d, J=6.6 Hz), 1.51 (6H, d, J=6 Hz), 2.48(3H, s), 2.73 (2H, t), 2.84 (2H, t), 3.46 (1H, m), 3.61 (2H, s), 3.94(3H, s), 4.90 (1H, m), 6.54 (1H, s), 6.88 (1H, d, J=7 Hz), 7.20 (1H, t,J=7 Hz), 7.90 (1H, d, J=7 Hz), 8.58 (1H, s), 9.29 (1H, br s).

PHARMACOGICAL DATA

1. Binding Assay Method

WO 92/22293 (SmithKline Beecham) discloses compounds havinganti-convulsant activity, including inter alia the compoundtrans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol(hereinafter referred to as Compound A). It as been found that thecompounds of WO 92/22293 bind to a novel receptor obtainable from ratforebrain tissue, as described in WO 96/18650 (SmithKline Beecham). Theaffinity of test compounds to the novel receptor site is assessed asfollows.

Method

Whole forebrain tissue is obtained from rats. The tissue is firsthomogenised in buffer (usually 50 mM Tris/HCl, pH 7.4). The homogenisedtissue is washed by centrifugation and resuspension in the same buffer,then stored at -70° C. until used.

To carry out the radioligand binding assay, aliquots of tissue preparedas above (usually at a concentration of 1-2 mg protein/ml) are mixedwith aliquots of [3H]-Compound A dissolved in buffer. The finalconcentration of [3H]-Compound A in the mixture is usually 20 nM. Themixture is incubated at room temperature for 1 hour. [3H]-Compound Abound to the tissue is then separated from unbound [3H]-Compound A byfiltration through Watman GF/B glass fibre filters. The filters are thenwashed rapidly with ice-cold buffer. The amount of radioactivity boundto the tissue trapped on the filters is measured by addition of liquidscintillation cocktail to the filters followed by counting in a liquidscintillation counter.

In order to determine the amount of "specific" binding of [3H]-CompoundA, parallel assays are carried out as above in which [3H]-Compound A andtissue are incubated together in the presence of unlabelled Compound A(usually 3 μM). The amount of binding of [3H]-Compound A remaining inthe presence of this unlabelled compound is defined as "non-specific"binding. This amount is subtracted from the total amount of[3H]-Compound A binding (i.e. that present in the absence of unlabelledcompound) to obtain the amount of "specific" binding of [3H]-Compound Ato the novel site.

The affinity of the binding of test compounds to the novel site can beestimated by incubating together [3H]-Compound A and tissue in thepresence of a range of concentrations of the compound to be tested. Thedecrease in the level of specific [3H]-Compound A binding as a result ofcompetition by increasing concentrations of the compound under test isplotted graphically, and non-linear regression analysis of theresulthant curve is used to provide an estimate of compound affinity interms of pKi value.

Results

Compounds of this invention were active in this test. For example,compounds of Examples 1, 7, 10, 13, 16, 17, 19, 20, 23, 25, 35, 37, 45,46, 49, 50, 52, 68, 70 and 71 gave pKi values greater than 7.

2. MEST Test

The maximal electroshock seizure threshold (MEST) test in rodents isparticularly sensitive for detecting potential anticonvulsantproperties¹. In this model, anticonvulsant agents elevate the thresholdto electrically-induced seizures whilst proconvulsants lower the seizurethreshold.

Method

Mice (naive male, Charles River, U.K. CD-1 strain, 25-30 g) are randomlyassigned to groups of 10-20 and dosed orally or intraperitoneally at adose volume of 10 ml/kg with various doses of compound (0.3-300 mg/kg)or vehicle. Mice are then subjected at 30 or 60 min post dose to asingle electroshock (0.1 sec, 50 Hz, sine wave form) administered viacorneal electrodes. The mean current and sthandard error required toinduce a tonic seizure in 50% (CC₅₀) of the mice in a particulartreatment group is determined by the `up and down` method of Dixon andMood (1948)². Sthatistical comparisons between vehicle- and drug-treatedgroups are made using the method of Litchfield and Wilcoxon (1949)³.

In control animals the CC₅₀ is usually 14-18 mA. Hence the first animalin the control group is subjected to a current of 16 mA. If a tonicseizure does not ensue, the current is increased for a subsequent mouse.If a tonic convulsion does occur, then the current is decreased, and soon until all the animals in the group have been tested.

The percentage increase or decrease in CC₅₀ for each group compared tothe control is calculated.

Studies are carried out using a Hugo Sachs Electronik Consthant CurrentShock Generator with totally variable control of shock level from 0 to300 mA and steps of 2 mA are usually used.

Drugs are suspended or dissolved in 1% methyl cellulose.

References

1. Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2, 145-181

2. Dixon, W. J. and Mood, A. M. (1948). J. Amer. Sthat. Assn., 43,109-126

3. Litchfield, J. T. and Wilcoxon, F.(1949). J. Pharmacol. exp. Ther.,96, 99-113

Results

Compounds of this invention dosed by the oral route as a suspension inmethyl cellulose and tested one hour post dosing showed an increase inseizure threshold. All compounds tested showed significant % increase at30 mg/kg po. Preferred compounds are hereinafter mentioned.

What is claimed is:
 1. A compound of formula (I) or pharmaceuticallyacceptable salt thereof: ##STR17## where n and p are independentlyintegers from 1 to 4 and (n+p) is from 2 to 5;R¹ is C₁₋₆ alkylO-; R² ishydrogen, halogen, CN, N₃, trifluoromethyldiazirinyl, CF₃, CF₃ O--, CF₃S--, CF₃ CO--, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-,C₁₋₆ alkylO-, C₁₋₆ alkylCO-, C₃₋₆ cycloalkylCO-, C₃₋₆ cycloalkyl-C₁₋₄alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C₁₋₄ alkyl-, C₁₋₆alkylS-, C₁₋₆ alkylSO₂ --, (C₁₋₄ alkyl)₂ NSO₂ -- or (C₁₋₄ alkyl)NHSO₂--; R³ is hydrogen, halogen, NO₂, CN, N₃, trifluoromethyldiazirinyl,C₁₋₆ alkylO-, C₁₋₆ alkylS-, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄ alkyl-, C₁₋₆ alkenyl, C₁₋₆ alkynyl, CF₃ CO--, C₁₋₆alkylCO-, C₃₋₆ cycloalkylCO-, C₃₋₆ cycloalkyl-C₁₋₄ alkylCO-, phenyl,phenoxy, benzyloxy, benzoyl, phenyl-C₁₋₄ alkyl-, or --NR⁵ R⁶ were R⁵ ishydrogen or C₁₋₄ alkyl, and R⁶ is hydrogen, C₁₋₄ alkyl, --CHO, --CO₂C₁₋₄ alkyl or --COC₁₋₄ alkyl; R⁴ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkenyl,or C₁₋₆ alkynyl; but excluding the compound2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide.2. A compound according to claim 1 in which R¹ is methoxy, ethoxy orn-propoxy.
 3. A compound according to claim 1 in which R² is hydrogen,methoxy, bromo, chloro, iodo, acetyl, pivaloyl, iso-butyroyl, benzoyl,trifluoromethyl, trifluoroacetyl, n-propylsulfonyl, isopropylsulfonyl ordimethylsulfamoyl.
 4. A compound according to claim 1 in which R³ ishydrogen, methyl, ethyl, n-butyl, phenyl, methoxy, ethoxy, iso-propyl,t-butyl, phenyl, methoxy, ethoxy, iso-propoxy, n-butoxy, phenoxy,benzyloxy, amino, acetylamino, nitro, benzoyl, iodobenzoyl, chloro orazido.
 5. A compound according to claim 1 in which R⁴ is hydrogen,methyl, ethyl or propyl.
 6. A compound as defined in claim 1 where R² orR³ are independently N₃, benzoyl, or trifluoromethyl-diazerinyl, and allother variables are as defined in claim
 1. 7.N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-chloro-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,4-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-chloro-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-acetylamino-5-bromo-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-bromo-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-azido-5-iodo-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-acetylamino-5-chloro-2-propoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-chloro-2-propoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-acetylamino-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-nitrobenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-amino-5-iodo-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-benzyloxy-5-chloro-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4,5-dichloro-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2,4-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-[3-(trifluoromethyl)-3H-diazirin-3-yl]-2-methoxybenzamideN-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-methylbenzamideN-(2-n-propyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamideN-(2-ethyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2,4-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-ethoxy-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,5-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-2-methoxy-4-methylbenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-dimethylsulfamoyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-benzoyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-4-acetylamino-5-chloro-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-8-yl)-4-amino-5-chloro-2-methoxybenzamideN-(2,3-dihydro-2-methyl-1H-isoindol-4-yl)-5-chloro-2,4-dimethoxybenzamide.N-(3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine-6-yl)-4-tert-butyl-2-methoxy-benzamideN-(1,2,3,4-tetrahydroisoquinolin-6-yl)-4-tert-butyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-tert-butyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-n-butyl-2-methoxy-5-chloro-benzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxy-5-chlorobenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxy-5-chloro-benzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-phenylbenzamideN-(1,2,3,4-tetrahydroisoquinolin-5-yl)-4-tert-butyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-iso-propyl-2-methoxy-benzamideN-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-4-tert-butyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-iso-propoxy-2-methoxy-benzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propyl-5-trifluoromethyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propoxy-2-methoxy-5-trifluoromethyl-benzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-iso-propyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iso-butyroyl-2-methoxy-benzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-pivaloyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chloro-2-methoxy-4-iso-propoxybenzamnideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-bromo-2,4-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-tert-butyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-methyl-5-trifluoromethylbenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2,4-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-chloro-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-iso-propoxy-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-dimethylsulfamoyl-2,4-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-iso-propylsulfonylbenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-phenylbenzamideN-(1,2,3,4-Tetrahydroisoquinolin-5-yl)-5-bromo-2,4-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-n-propylsulfonylbenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2,4-dimethoxy-5-trifluoromethylbenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-methyl-5-trifluoromethylbenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-acetyl-2,4-dimethoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-bromo-4-ethyl-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-ethyl-2-methoxy-5-trifluoromethylbenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-n-butoxy-5-chloro-2-methoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-iso-propyloxy-5-acetyl-benzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-chloro-2-methoxy-4-iso-propoxybenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-iodo-4-trifluoromethyldiazirinylbenzamideN-(1,2,3,4-tetrahydroisoquinolin-5-yl)-4-azido-5-iodo-2-methoxybenzamideN-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iodo-2-methoxy-4-trifluoromethyldiazirinylbenzamideN-(7-iodo-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamideN-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-benzoyl-2-methoxybenzamideN-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-5-benzoyl-2-methoxybenzamideN-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-trifluoromethyldiazirinylbenzamideN-(5-iodo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-5-trifluoromethyldiazirinylbenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoroacetylbenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoroacetylbenzamideN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-4-trifluoromethyldiazirinylbenzamideN-(1,2,3,4-tetrahydroisoquinolin-7-yl)-5-iodo-2-methoxy-4-trifluoromethyldiazirinylbenzamideN-(1,2,3,4-tetrahydroisoquinolin-5-yl)-5-(4-iodobenzoyl)-2-methoxybenzamideN-(7-iodo-1,2,3,4-tetrahydroisoquinolin-5-yl)-2-methoxy-5-trifluoromethyldiazirinylbenzamide;N-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-chloro-2-methoxybenzamideN-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-methoxy-4-methylthiobenzamideN-(8-Fluoro-2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-t-butyl-2-methoxybenzamideN-(2-Methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-5-iso-butyroyl-4-iso-propoxy-2-methoxybenzamide,andN-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-4-n-butoxy-2-methoxybenzamide.8. A pharmaceutical composition for use in the treatment and/orprevention of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substhances ofabuse, disorders treatable and/or preventable with anti-convulsiveagents, Parkinson's disease, phychosis, migraine, cerebral ischaemia,Alzheimer's disease and other degenerative diseases, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders, tics, traumatic brain injury, tinnitus,neuralgia, trigeminal neuralgia, neuropathic pain, dental pain, cancerpain, inappropriate neuronal activity resulting in neurodysthesias indiseases, ataxias, muscular rigidity (spacicity), temporomandibularjoint dysfunction, and amyptrophic lateral sclerosis (ALS) whichcomprises a compound of formula (I) as defined in claim 1, withoutexcluding2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide,or a pharmaceutically acceptable salt or solvate thereof, and apharmaceutically acceptable carrier.
 9. A method of treatment and/orprevention of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substhances ofabuse, disorders treatable and/or preventable with anti-convulsiveagents, Parkinson's disease, phychosis, migraine, cerebral ischaemia,Alzheimer's disease and other degenerative diseases, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders, tics, traumatic brain injury, tinnitus,neuralgia, trigeminal neuralgia, neuropathic pain, dental pain, cancerpain, inappropriate neuronal activity resulting in neurodysthesias indiseases, ataxias, muscular rigidity (spacicity), temporomandibularjoint dysfunction, and amyptrophic lateral sclerosis (ALS) comprisingadministering to the sufferer in need thereof an effective or preventiveamount of a compound of formula (I) as defined in claim 1, withoutexcluding2,4,5-trimethoxy-N-(2-methyl-1,2,3,4-tetrahydroisoquinolin-5-yl)benzamide,or a pharmaceutically acceptable salt or solvate thereof.
 10. A processfor the preparation of a compound of formula (I), which comprisesreacting a compound of formula (II) ##STR18## where n and p areindependently integers from 1 to 4 and (n+p) is from 2 to 5; and R^(4A)is R⁴ wherein R⁴ is hydrogen, C₁₋₆ alky, C₁₋₆ alkenyl, or C₁₋₆ alkynyl,or a group convertible to R⁴ with a compound of formula (III) ##STR19##where Y is Cl or OH, and R^(1A), R^(2A) and R^(3A) are respectively R¹,R² and R³ wherein:R¹ is C₁₋₆ alkylO, R² is hydrogen, halogen, CN, N₃,trifluoromethyldiazirinyl, CF₃, CF₃ O--, CF₃ S--, CF₃ CO--, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalky-C₁₋₄ alkyl-, C₁₋₆ alkylO, C₁₋₆-alkylCO-, C₃₋₆ cycloalkylCO-, C₃₋₆ cycloalkyl-C₁₋₄ alkylCO-; phenyl,phenoxy, benzyloxy, benzoyl, phenol-C₁₋₄ alkyl-, C₁₋₆ alkylS-, C₁₋₆alkylSO₂ --, (C₁₋₄ alkyl)₂ NSO₂ -- or (C₁₋₄ alkyl)NHSO₂ --; R³ ishydrogen, halogen, NO₂, CN, N₃, trifluoromethyldiazirinyl, C₁₋₆ alkylO-,C₁₋₆ alkylS-, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-,C₁₋₆ aIkenyl, C₁₋₆ alkynyl, CF₃ CO--, C₁₋₆ alkylCO-, C₃₋₆ cycloalkylCO-,C₃₋₆ -cycloalkyl-C₁₋₄ alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C₁₋₄ alkyl-, or --NR₅ R₆ where R₅ is hydrogen or C₁₋₄ alkyl, andR₆ is hydrogen, C₁₋₄ alkyl, --CHO, --CO₂ C₁₋₄ alkyl or --COC₁₋₄ alkyl;orgroups convertible to R¹, R² and R³ ; and where required converting aR^(1A), R^(2A), R^(3A) or R^(4A) group to a R¹, R², R³ or R⁴ group,converting one R¹, R², R³ or R⁴ group to another R¹, R², R³ or R⁴ group,converting a hydrochloride salt to the free base or anotherpharmaceutically acceptable salt or converting the free base to apharmaceutically acceptable salt.
 11. A pharmaceutical compositionaccording to claim 8 wherein the substhances of abuse is chosen from thegroup comprising cocaine, nicotine, alcohol and benzodiazepines.
 12. Apharmaceutical composition according to claim 8 wherein the disordertreatable and/or preventable with anti-convulsive agents is chosen fromthe group comprising epilepsy and post-traumatic epilepsy.
 13. Apharmaceutical composition according to claim 8 wherein the sleepdisorder is chosen from the group comprising circadian rhythm disorders,insomnia and narcolepsy.
 14. A pharmaceutical composition according toclaim 8 wherein the disease causing inappropriate neuronal activityresulting in neurodysthesias is chosen from the group comprisingdiabetes, MS and motor neuron disease.
 15. A pharmaceutical compositionaccording to claim 8 wherein the tic is Giles de la Tourette's syndrome.16. A method of treatment according to claim 9 wherein the substhancesof abuse is chosen from the group comprising cocaine, nicotine, alcoholand benzodiazepines.
 17. A method of treatment according to claim 9wherein the disorder treatable and/or preventable with anti-convulsiveagents is chosen from the group comprising epilepsy and post-traumaticepilepsy.
 18. A method of treatment according to claim 9 wherein thesleep disorder is chosen from the group comprising circadian rhythmdisorders, insomnia and narcolepsy.
 19. A method of treatment accordingto claim 9 wherein the disease causing inappropriate neuronal activityresulting in neurodysthesias is chosen from the group comprisingdiabetes, MS and motor neuron disease.
 20. A method of treatmentaccording to claim 9 wherein the tic is Giles de la Tourette's syndrome.